Welcome to the University of Liverpool Repository - The ...
Antimalarial Pharmacology and Therapeutics of AtovaquoneGemma L Nixon1*, Darren M Moss1*, Alison E Shone1, David Lalloo1, Nicholas Fisher1, Paul M O’Neill2, Stephen A Ward1 and Giancarlo A Biagini1**1Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK 2Department of Chemistry, Liverpool University, Liverpool L69 7ZD, UK* These authors contributed equally to the study** Author for correspondence. Tel:+441517053151, Fax:+441517053371, Biagini@liverpool.ac.ukKey Words: Malaria, Drug Development, Mechanism of Action, Resistance, drug interactions.SummaryAtovaquone is used as a fixed dose combination with proguanil (MalaroneTM), either for treating children and adults with uncomplicated malaria or as a chemoprophylaxis for preventing malaria in travellers. Indeed in the US, between 2009-2011, MalaroneTM prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for MalaroneTM will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones, with a related pharmacophore to atovaquone, at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.Introduction Atovaquone is the end product of half a century of research by many groups who researched the antiparasitic properties of numerous structurally related compounds.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA 1-6 Currently Atovaquone is used as a fixed dose combination with proguanil (MalaroneTM), for the treatment of children and adults with uncomplicated malaria or as a chemoprophylactic agent for preventing malaria in travellers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc2VpLUFrb3RvPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc2VpLUFrb3RvPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh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=
ADDIN EN.CITE.DATA 7, 8 Between 2009 and 2011 in the US MalaroneTM accounted for 70% of all antimalarial pre-travel prescriptions.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYVJvY3F1ZTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYVJvY3F1ZTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE.DATA 9 The development of atovaquone as an antimalarial drug began over 50 years ago when the outbreak of World War 2 caused substantial shortages in the supply of quinine. ADDIN EN.CITE <EndNote><Cite><Author>Fieser</Author><Year>1948</Year><RecNum>5</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fieser, L. F.</author><author>Richardson, A. P.</author></authors></contributors><titles><title>Naphthoquinone Antimalarials .2. Correlation of Structure and Activity against P-Lophurae in Ducks</title><secondary-title>Journal of the American Chemical Society</secondary-title><alt-title>J Am Chem Soc</alt-title></titles><periodical><full-title>Journal of the American Chemical Society</full-title><abbr-1>J Am Chem Soc</abbr-1></periodical><alt-periodical><full-title>Journal of the American Chemical Society</full-title><abbr-1>J Am Chem Soc</abbr-1></alt-periodical><pages>3156-3165</pages><volume>70</volume><number>10</number><dates><year>1948</year></dates><isbn>0002-7863</isbn><accession-num>ISI:A1948UB19400002</accession-num><urls><related-urls><url><Go to ISI>://A1948UB19400002</url></related-urls></urls><language>English</language></record></Cite></EndNote>10 Intense efforts in America led to thousands of structurally diverse compounds being investigated, several of which were hydroxynaphthoquinones. Modest antimalarial activity when administered to ducks infected with Plasmodium lophurae resulted in a robust lead optimisation programme generating more than 300 quinones, some of which demonstrated greater activity than quinine in the duck assay. However, when administered to malaria patients these compounds were devoid of any activity due to poor absorption and rapid metabolism.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaWVzZXI8L0F1dGhvcj48WWVhcj4xOTQ4PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaWVzZXI8L0F1dGhvcj48WWVhcj4xOTQ4PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 11, 12 Attempts to solve these problems and produce an orally active quinine were unsuccessful both then and when the problem was re-visited in the 1960s. ADDIN EN.CITE <EndNote><Cite><Author>Fieser</Author><Year>1967</Year><RecNum>8</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fieser, L. F.</author><author>Schirmer, J. P.</author><author>Archer, S.</author><author>Lorenz, R. R.</author><author>Pfaffenb.Pi</author></authors></contributors><titles><title>Naphthoquinone Antimalarials .29. 2-Hydroxy-3-(Omega-Cyclohexylalkyl)-1,4-Naphthoquinones</title><secondary-title>Journal of Medicinal Chemistry</secondary-title><alt-title>J Med Chem</alt-title></titles><periodical><full-title>Journal of Medicinal Chemistry</full-title><abbr-1>J Med Chem</abbr-1></periodical><alt-periodical><full-title>Journal of Medicinal Chemistry</full-title><abbr-1>J Med Chem</abbr-1></alt-periodical><pages>513-&</pages><volume>10</volume><number>4</number><dates><year>1967</year></dates><isbn>0022-2623</isbn><accession-num>ISI:A19679546300001</accession-num><urls><related-urls><url><Go to ISI>://A19679546300001</url></related-urls></urls><language>English</language></record></Cite></EndNote>13 Research in the 1960s did however lead the development of Lapinone (1), which was given intravenously and had activity against Plasmodium vivax (Figure 1). ADDIN EN.CITE <EndNote><Cite><Author>Fawaz</Author><Year>1951</Year><RecNum>9</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fawaz, G.</author><author>Haddad, F. S.</author></authors></contributors><titles><title>The Effect of Lapinone (M-2350) on P-Vivax Infection in Man</title><secondary-title>American Journal of Tropical Medicine</secondary-title><alt-title>Am J Trop Med</alt-title></titles><periodical><full-title>American Journal of Tropical Medicine</full-title><abbr-1>Am J Trop Med</abbr-1></periodical><alt-periodical><full-title>American Journal of Tropical Medicine</full-title><abbr-1>Am J Trop Med</abbr-1></alt-periodical><pages>569-571</pages><volume>31</volume><number>5</number><dates><year>1951</year></dates><isbn>0002-9637</isbn><accession-num>ISI:A1951UY64200005</accession-num><urls><related-urls><url><Go to ISI>://A1951UY64200005</url></related-urls></urls><language>English</language></record></Cite></EndNote>14The use of quinones as antimalarial agents was then reinvestigated in the 1980s by a group at the Wellcome Research Laboratories. More meaningful studies could be carried out at this time due to the development of test systems using the human parasite Plasmodium falciparum in vitro or in Aotus monkeys. The aim of this study was to design a quinone with good antimalarial activity against P. falciparum combined with good metabolic stability in humans. Several 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone analogues (2 and 3) were synthesised with the metabolically labile 4’ position of the cyclohexyl ring substituted with a range of groups.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 15, 16 Several of these quinones demonstrated a potency of ~1 nM towards P. falciparum in vitro but only atovaquone (4) was inert to human liver microsomes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWRzb248L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 17, 18 The trans isomer of atovaquone is substantially more potent than corresponding cis isomer. The chemical synthesis of atovaquone was originally disclosed in 1991 in US patent No.4981874. This route gave a poor yield of 4% atovaquone calculated from only the last two steps (Figure 2A). ADDIN EN.CITE <EndNote><Cite><Author>S.Latter</Author><Year>1991</Year><RecNum>14</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">14</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Victoria S.Latter </author><author>Winston E. Gutteridge</author></authors></contributors><titles><title>Medicaments US 4981874
</title></titles><number>4981874</number><dates><year>1991</year></dates><pub-location>United States Patent </pub-location><urls></urls></record></Cite></EndNote>19Williams and Clark then published a variant of this methodology (Figure 2B) in which oxalate (11) was used to produce racemic compound (9) in 43% yield and the ester by-product (12) in 38% yield. ADDIN EN.CITE <EndNote><Cite><Author>Williams</Author><Year>1998</Year><RecNum>15</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Williams, D. R.</author><author>Clark, M. P.</author></authors></contributors><auth-address>Williams, DR
Indiana Univ, Dept Chem, Bloomington, IN 47405 USA
Indiana Univ, Dept Chem, Bloomington, IN 47405 USA
Indiana Univ, Dept Chem, Bloomington, IN 47405 USA</auth-address><titles><title>Synthesis of atovaquone</title><secondary-title>Tetrahedron Letters</secondary-title><alt-title>Tetrahedron Lett</alt-title></titles><periodical><full-title>Tetrahedron Letters</full-title><abbr-1>Tetrahedron Lett</abbr-1></periodical><alt-periodical><full-title>Tetrahedron Letters</full-title><abbr-1>Tetrahedron Lett</abbr-1></alt-periodical><pages>7629-7632</pages><volume>39</volume><number>42</number><dates><year>1998</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>0040-4039</isbn><accession-num>ISI:000076220800004</accession-num><urls><related-urls><url><Go to ISI>://000076220800004</url></related-urls></urls><language>English</language></record></Cite></EndNote>20 Conversion to atovaquone was then achieved as described in Figure 2A. The disadvantages of this process are the column chromatography required to separate (9) from (12) and the same poor yield problem will still prevail in the final two steps. Both processes described so far also involve the use of silver nitrate, a heavy metal which can be difficult to remove and whose use is tightly regulated. The recently patented (WO 2010/001379) synthesis seen in Figure 2C offers an improved synthesis of atovaquone as it is higher yielding and doesn’t involve the use of heavy metals. ADDIN EN.CITE <EndNote><Cite><Author>Zhu</Author><Year>2010</Year><RecNum>16</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">16</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Fuqiang Zhu</author><author>He Qiao</author><author>Michel Bekhazi</author></authors><secondary-authors><author>World Intellectual Property Organization</author></secondary-authors></contributors><titles><title>A Process for Preparing Atovaquone and Associate Intermediates WO/2010/001379
</title></titles><number>WO/2010/001379</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>21A common problem with all the routes so far is that large amounts of the potentially useful, yet significantly less potent cis isomer of atovaquone are disregarded as only the trans isomer is required. There are two literature procedures that address this problem. Reacting the cis isomer of atovaquone, atovaquone intermediates or isomeric mixtures thereof with a strong acid results in a clean epimerization to the corresponding trans isomer and thus to high yields of trans atovaquone. ADDIN EN.CITE <EndNote><Cite><Author>Zhu</Author><Year>2010</Year><RecNum>17</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>17</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">17</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Fuqiang Zhu</author><author>Michel Bekhazi</author></authors></contributors><titles><title>PROCESS FOR THE EPIMERIZATION OF ATOVAQUONE ISOMER, ATOVAQUONE INTERMEDIATES AND MIXTURE THEREOF WO/2010/001378</title></titles><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>22 Heating the cis isomer at reflux in organic solvent also carries out this transformation. ADDIN EN.CITE <EndNote><Cite><Author>Verma</Author><Year>2008</Year><RecNum>18</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">18</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>Shyam Verma</author><author>Dhimant Patel</author><author>Shriprakash Dwivedi</author></authors></contributors><titles><title>PROCESS FOR PREPARATION OF ATOVAQUONE AND THE CONVERSION OF CIS-ISOMER TO TRANS- ISOMER WO/2008/122988</title></titles><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>23With the patent relating to Malarone due to expire in 2013 the synthesis of atovaquone will be exploited to its full potential as generic versions of the drug are likely to become common place. This will in turn have a marked effect on the cost of goods as currently the high cost of atovaquone is frequently prohibitive in its use by the endemic population within countries affected by malaria. Increased availability and use of the drug will also have an effect on the clinical efficacy of atovaquone and factors such as access, sustainability, and resistance need to be considered. ADDIN EN.CITE <EndNote><Cite><Author>Baggish</Author><Year>2002</Year><RecNum>14513</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>14513</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">14513</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baggish, A. L.</author><author>Hill, D. R.</author></authors></contributors><auth-address>University of Connecticut School of Medicine, Farmington, Connecticut, USA.</auth-address><titles><title>Antiparasitic agent atovaquone</title><secondary-title>Antimicrob Agents Chemother</secondary-title></titles><periodical><full-title>Antimicrobial agents and chemotherapy</full-title><abbr-1>Antimicrob Agents Chemother</abbr-1></periodical><pages>1163-73</pages><volume>46</volume><number>5</number><keywords><keyword>Animal</keyword><keyword>Antifungal Agents/pharmacology/*therapeutic use</keyword><keyword>Antiprotozoal Agents/pharmacology/*therapeutic use</keyword><keyword>Babesia/drug effects</keyword><keyword>Human</keyword><keyword>Naphthoquinones/pharmacology/*therapeutic use</keyword><keyword>Plasmodium/drug effects</keyword><keyword>Pneumocystis carinii/drug effects</keyword><keyword>Pneumonia, Pneumocystis carinii/*drug therapy</keyword><keyword>Protozoan Infections/*drug therapy/parasitology</keyword><keyword>Randomized Controlled Trials</keyword><keyword>Toxoplasma/drug effects</keyword></keywords><dates><year>2002</year><pub-dates><date>May</date></pub-dates></dates><accession-num>11959541</accession-num><urls><related-urls><url> Furthermore, the malaria scientific community has a number of antimalarial quinolones, with a related pharmacophore to atovaquone, at various stages of pre-clinical development.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFnaW5pPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFnaW5pPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
UmVjTnVtPjE4Njc0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw
dCI+MjUtMzA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODY3NDwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9Inhzcno5cHIwdDVz
OTJ3ZWZ2emh4eHR0Y3ZlYTJ6eGZwMHZmciI+MTg2NzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm
LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48
YXV0aG9ycz48YXV0aG9yPkJpYWdpbmksIEcuIEEuPC9hdXRob3I+PGF1dGhvcj5GaXNoZXIsIE4u
PC9hdXRob3I+PGF1dGhvcj5TaG9uZSwgQS4gRS48L2F1dGhvcj48YXV0aG9yPk11YmFyYWtpLCBN
LiBBLjwvYXV0aG9yPjxhdXRob3I+U3JpdmFzdGF2YSwgQS48L2F1dGhvcj48YXV0aG9yPkhpbGws
IEEuPC9hdXRob3I+PGF1dGhvcj5BbnRvaW5lLCBULjwvYXV0aG9yPjxhdXRob3I+V2FybWFuLCBB
LiBKLjwvYXV0aG9yPjxhdXRob3I+RGF2aWVzLCBKLjwvYXV0aG9yPjxhdXRob3I+UGlkYXRoYWxh
LCBDLjwvYXV0aG9yPjxhdXRob3I+QW1ld3UsIFIuIEsuPC9hdXRob3I+PGF1dGhvcj5MZXVuZywg
Uy4gQy48L2F1dGhvcj48YXV0aG9yPlNoYXJtYSwgUi48L2F1dGhvcj48YXV0aG9yPkdpYmJvbnMs
IFAuPC9hdXRob3I+PGF1dGhvcj5Ib25nLCBELiBXLjwvYXV0aG9yPjxhdXRob3I+UGFjb3JlbCwg
Qi48L2F1dGhvcj48YXV0aG9yPkxhd3JlbnNvbiwgQS4gUy48L2F1dGhvcj48YXV0aG9yPkNoYXJv
ZW5zdXR0aGl2YXJha3VsLCBTLjwvYXV0aG9yPjxhdXRob3I+VGF5bG9yLCBMLjwvYXV0aG9yPjxh
dXRob3I+QmVyZ2VyLCBPLjwvYXV0aG9yPjxhdXRob3I+TWJla2VhbmksIEEuPC9hdXRob3I+PGF1
dGhvcj5TdG9ja3MsIFAuIEEuPC9hdXRob3I+PGF1dGhvcj5OaXhvbiwgRy4gTC48L2F1dGhvcj48
YXV0aG9yPkNoYWR3aWNrLCBKLjwvYXV0aG9yPjxhdXRob3I+SGVtaW5nd2F5LCBKLjwvYXV0aG9y
PjxhdXRob3I+RGVsdmVzLCBNLiBKLjwvYXV0aG9yPjxhdXRob3I+U2luZGVuLCBSLiBFLjwvYXV0
aG9yPjxhdXRob3I+WmVlbWFuLCBBLiBNLjwvYXV0aG9yPjxhdXRob3I+S29ja2VuLCBDLiBILiBN
LjwvYXV0aG9yPjxhdXRob3I+QmVycnksIE4uIEcuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7TmVp
bGwsIFAuIE0uPC9hdXRob3I+PGF1dGhvcj5XYXJkLCBTLiBBLjwvYXV0aG9yPjwvYXV0aG9ycz48
L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkhlbWluZ3dheSwgSiYjeEQ7VW5pdiBMaXZlcnBv
b2wsIExpdmVycG9vbCBTY2ggVHJvcCBNZWQsIExpdmVycG9vbCBMMyA1UUEsIE1lcnNleXNpZGUs
IEVuZ2xhbmQmI3hEO1VuaXYgTGl2ZXJwb29sLCBMaXZlcnBvb2wgU2NoIFRyb3AgTWVkLCBMaXZl
cnBvb2wgTDMgNVFBLCBNZXJzZXlzaWRlLCBFbmdsYW5kJiN4RDtVbml2IExpdmVycG9vbCwgTGl2
ZXJwb29sIFNjaCBUcm9wIE1lZCwgTGl2ZXJwb29sIEwzIDVRQSwgTWVyc2V5c2lkZSwgRW5nbGFu
ZCYjeEQ7VW5pdiBMaXZlcnBvb2wsIERlcHQgQ2hlbSwgTGl2ZXJwb29sIEw2OSA3WkQsIE1lcnNl
eXNpZGUsIEVuZ2xhbmQmI3hEO1VuaXYgTG9uZG9uIEltcGVyaWFsIENvbGwgU2NpIFRlY2hub2wg
JmFtcDsgTWVkLCBEZXB0IExpZmUgU2NpLCBMb25kb24gU1c3IDJBWiwgRW5nbGFuZCYjeEQ7Qmlv
bWVkIFByaW1hdGUgUmVzIEN0ciwgRGVwdCBQYXJhc2l0b2wsIE5MLTIyODAgR0ggUmlqc3dpamss
IE5ldGhlcmxhbmRzPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R2VuZXJhdGlvbiBvZiBx
dWlub2xvbmUgYW50aW1hbGFyaWFscyB0YXJnZXRpbmcgdGhlIFBsYXNtb2RpdW0gZmFsY2lwYXJ1
bSBtaXRvY2hvbmRyaWFsIHJlc3BpcmF0b3J5IGNoYWluIGZvciB0aGUgdHJlYXRtZW50IGFuZCBw
cm9waHlsYXhpcyBvZiBtYWxhcmlhPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlByb2NlZWRpbmdz
IG9mIHRoZSBOYXRpb25hbCBBY2FkZW15IG9mIFNjaWVuY2VzIG9mIHRoZSBVbml0ZWQgU3RhdGVz
IG9mIEFtZXJpY2E8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlAgTmF0bCBBY2FkIFNjaSBV
U0E8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qcm9jZWVkaW5n
cyBvZiB0aGUgTmF0aW9uYWwgQWNhZGVteSBvZiBTY2llbmNlcyBvZiB0aGUgVW5pdGVkIFN0YXRl
cyBvZiBBbWVyaWNhPC9mdWxsLXRpdGxlPjxhYmJyLTE+UHJvYyBOYXRsIEFjYWQgU2NpIFUgUyBB
PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz44Mjk4LTgzMDM8L3BhZ2VzPjx2b2x1bWU+MTA5
PC92b2x1bWU+PG51bWJlcj4yMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5kcnVnIGRpc2Nv
dmVyeTwva2V5d29yZD48a2V5d29yZD5wYXJhc2l0ZTwva2V5d29yZD48a2V5d29yZD5jb21wbGV4
PC9rZXl3b3JkPjxrZXl3b3JkPmluaGliaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+YXRvdmFxdW9u
ZTwva2V5d29yZD48a2V5d29yZD5yZXNpc3RhbmNlPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz
Pjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMjI8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4wMDI3LTg0MjQ8L2lzYm4+PGFjY2Vzc2lvbi1udW0+SVNJOjAwMDMw
NDQ0NTgwMDA3NjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+Jmx0O0dv
IHRvIElTSSZndDs6Ly8wMDAzMDQ0NDU4MDAwNzY8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPkRvaSAxMC4xMDczL1BuYXMuMTIwNTY1MTEwOTwvZWxl
Y3Ryb25pYy1yZXNvdXJjZS1udW0+PGxhbmd1YWdlPkVuZ2xpc2g8L2xhbmd1YWdlPjwvcmVjb3Jk
PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlpoYW5nPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
TnVtPjIxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yMTwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBwZjJ2bWQ1ZGR4
d2RwZjJ2eCI+MjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBB
cnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlpoYW5n
LCBZLjwvYXV0aG9yPjxhdXRob3I+Q2xhcmssIEouIEEuPC9hdXRob3I+PGF1dGhvcj5Db25uZWxs
eSwgTS4gQy48L2F1dGhvcj48YXV0aG9yPlpodSwgRi48L2F1dGhvcj48YXV0aG9yPk1pbiwgSi48
L2F1dGhvcj48YXV0aG9yPkd1aWd1ZW1kZSwgVy4gQS48L2F1dGhvcj48YXV0aG9yPlByYWRoYW4s
IEEuPC9hdXRob3I+PGF1dGhvcj5JeWVyLCBMLjwvYXV0aG9yPjxhdXRob3I+RnVyaW1za3ksIEEu
PC9hdXRob3I+PGF1dGhvcj5Hb3csIEouPC9hdXRob3I+PGF1dGhvcj5QYXJtYW4sIFQuPC9hdXRo
b3I+PGF1dGhvcj5FbCBNYXpvdW5pLCBGLjwvYXV0aG9yPjxhdXRob3I+UGhpbGxpcHMsIE0uIEEu
PC9hdXRob3I+PGF1dGhvcj5LeWxlLCBELiBFLjwvYXV0aG9yPjxhdXRob3I+TWlyc2FsaXMsIEou
PC9hdXRob3I+PGF1dGhvcj5HdXksIFIuIEsuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0
b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDaGVtaWNhbCBCaW9sb2d5IGFuZCBUaGVy
YXBldXRpY3MsIFN0LiBKdWRlIENoaWxkcmVuJmFwb3M7cyBSZXNlYXJjaCBIb3NwaXRhbCAsIDI2
MiBEYW5ueSBUaG9tYXMgUGxhY2UsIE1lbXBoaXMsIFRlbm5lc3NlZSAzODEwNSwgVW5pdGVkIFN0
YXRlcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5MZWFkIE9wdGltaXphdGlvbiBvZiAz
LUNhcmJveHlsLTQoMUgpLVF1aW5vbG9uZXMgdG8gRGVsaXZlciBPcmFsbHkgQmlvYXZhaWxhYmxl
IEFudGltYWxhcmlhbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBvZiBtZWRpY2lu
YWwgY2hlbWlzdHJ5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG1lZGlj
aW5hbCBjaGVtaXN0cnk8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5Kb3VybmFsIG9mIE1lZGljaW5hbCBDaGVtaXN0cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1l
ZCBDaGVtPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5K
b3VybmFsIG9mIE1lZGljaW5hbCBDaGVtaXN0cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1lZCBD
aGVtPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+NDIwNS0xOTwvcGFnZXM+PHZvbHVt
ZT41NTwvdm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxlZGl0aW9uPjIwMTIvMDMvMjM8L2VkaXRp
b24+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTA8L2RhdGU+
PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTIwLTQ4MDQgKEVsZWN0cm9uaWMpJiN4RDswMDIy
LTI2MjMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIyNDM1NTk5PC9hY2Nlc3Npb24t
bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3Yv
cHVibWVkLzIyNDM1NTk5PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPjMzNDk4
MTg8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMjEvam0yMDE2NDJ6PC9l
bGVjdHJvbmljLXJlc291cmNlLW51bT48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48
L0NpdGU+PENpdGU+PEF1dGhvcj5Dcm9zczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051
bT4yMjwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjI8L3JlYy1udW1iZXI+PGZvcmVpZ24t
a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSIyc3Jhdzl3eHM1NXI1NWVyNTUwcGYydm1kNWRkeHdk
cGYydngiPjIyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0
aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Dcm9zcywg
Ui4gTS48L2F1dGhvcj48YXV0aG9yPk5hbWVsaWtvbmRhLCBOLiBLLjwvYXV0aG9yPjxhdXRob3I+
TXV0a2EsIFQuIFMuPC9hdXRob3I+PGF1dGhvcj5MdW9uZywgTC48L2F1dGhvcj48YXV0aG9yPkt5
bGUsIEQuIEUuPC9hdXRob3I+PGF1dGhvcj5NYW5ldHNjaCwgUi48L2F1dGhvcj48L2F1dGhvcnM+
PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENoZW1pc3RyeSwgVW5p
dmVyc2l0eSBvZiBTb3V0aCBGbG9yaWRhLCBDSEUgMjA1LCA0MjAyIEUuIEZvd2xlciBBdmVudWUs
IFRhbXBhLCBGbG9yaWRhIDMzNjIwLCBVbml0ZWQgU3RhdGVzLjwvYXV0aC1hZGRyZXNzPjx0aXRs
ZXM+PHRpdGxlPlN5bnRoZXNpcywgYW50aW1hbGFyaWFsIGFjdGl2aXR5LCBhbmQgc3RydWN0dXJl
LWFjdGl2aXR5IHJlbGF0aW9uc2hpcCBvZiA3LSgyLXBoZW5veHlldGhveHkpLTQoMUgpLXF1aW5v
bG9uZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBvZiBtZWRpY2luYWwgY2hlbWlz
dHJ5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG1lZGljaW5hbCBjaGVt
aXN0cnk8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Kb3VybmFs
IG9mIE1lZGljaW5hbCBDaGVtaXN0cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1lZCBDaGVtPC9h
YmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Kb3VybmFsIG9m
IE1lZGljaW5hbCBDaGVtaXN0cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1lZCBDaGVtPC9hYmJy
LTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+ODMyMS03PC9wYWdlcz48dm9sdW1lPjU0PC92b2x1
bWU+PG51bWJlcj4yNDwvbnVtYmVyPjxlZGl0aW9uPjIwMTEvMTEvMjU8L2VkaXRpb24+PGtleXdv
cmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW1hbGFyaWFscy8qY2hl
bWljYWwgc3ludGhlc2lzL2NoZW1pc3RyeS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+
QXRvdmFxdW9uZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBMaW5lPC9rZXl3
b3JkPjxrZXl3b3JkPkRydWcgUmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3
b3JkPjxrZXl3b3JkPlBsYXNtb2RpdW0gZmFsY2lwYXJ1bS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+
PGtleXdvcmQ+UXVpbm9sb25lcy8qY2hlbWljYWwgc3ludGhlc2lzL2NoZW1pc3RyeS9waGFybWFj
b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U3RydWN0dXJlLUFjdGl2aXR5IFJlbGF0aW9uc2hpcDwv
a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRh
dGU+RGVjIDIyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMC00ODA0IChFbGVj
dHJvbmljKSYjeEQ7MDAyMi0yNjIzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjEx
MTkwNzwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPlJlc2VhcmNoIFN1cHBvcnQsIE5vbi1VLlMu
IEdvdiZhcG9zO3Q8L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3
dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMjExMTkwNzwvdXJsPjwvcmVsYXRlZC11cmxzPjwv
dXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAyMS9qbTIwMDcxOG08L2VsZWN0cm9u
aWMtcmVzb3VyY2UtbnVtPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48
Q2l0ZT48QXV0aG9yPkJhcnRvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJlY051bT4yMzwv
UmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48
a2V5IGFwcD0iRU4iIGRiLWlkPSIyc3Jhdzl3eHM1NXI1NWVyNTUwcGYydm1kNWRkeHdkcGYydngi
PjIzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+
MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj48c3R5bGUgZmFjZT0i
bm9ybWFsIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj5CYXJ0b24sIFYuPC9zdHlsZT48L2F1
dGhvcj48YXV0aG9yPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZldGljYSIgc2l6ZT0i
MTIiPkZpc2hlciwgTi48L3N0eWxlPjwvYXV0aG9yPjxhdXRob3I+PHN0eWxlIGZhY2U9Im5vcm1h
bCIgZm9udD0iSGVsdmV0aWNhIiBzaXplPSIxMiI+QmlhZ2luaSwgRy4gQS48L3N0eWxlPjwvYXV0
aG9yPjxhdXRob3I+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iSGVsdmV0aWNhIiBzaXplPSIx
MiI+V2FyZCwgUy4gQS48L3N0eWxlPjwvYXV0aG9yPjxhdXRob3I+PHN0eWxlIGZhY2U9Im5vcm1h
bCIgZm9udD0iSGVsdmV0aWNhIiBzaXplPSIxMiI+TyZhcG9zO05laWxsLCBQLiBNLjwvc3R5bGU+
PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+PHN0eWxlIGZh
Y2U9Im5vcm1hbCIgZm9udD0iSGVsdmV0aWNhIiBzaXplPSIxMiI+RGVwYXJ0bWVudCBvZiBDaGVt
aXN0cnksIFVuaXZlcnNpdHkgb2YgTGl2ZXJwb29sLCBPeGZvcmQgU3RyZWV0LCBMaXZlcnBvb2wg
TDY5IDdaRCwgVUsuPC9zdHlsZT48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT48c3R5bGUg
ZmFjZT0ibm9ybWFsIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj5JbmhpYml0aW5nIFBsYXNt
b2RpdW0gY3l0b2Nocm9tZSBiYzE6IGEgY29tcGxleCBpc3N1ZTwvc3R5bGU+PC90aXRsZT48c2Vj
b25kYXJ5LXRpdGxlPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZldGljYSIgc2l6ZT0i
MTIiPkN1cnIgT3BpbiBDaGVtIEJpb2w8L3N0eWxlPjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz
PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkN1cnIgT3BpbiBDaGVtIEJpb2w8L2Z1bGwtdGl0bGU+
PC9wZXJpb2RpY2FsPjxwYWdlcz48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJIZWx2ZXRpY2Ei
IHNpemU9IjEyIj40NDAtNjwvc3R5bGU+PC9wYWdlcz48dm9sdW1lPjxzdHlsZSBmYWNlPSJub3Jt
YWwiIGZvbnQ9IkhlbHZldGljYSIgc2l6ZT0iMTIiPjE0PC9zdHlsZT48L3ZvbHVtZT48bnVtYmVy
PjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZldGljYSIgc2l6ZT0iMTIiPjQ8L3N0eWxl
PjwvbnVtYmVyPjxlZGl0aW9uPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZldGljYSIg
c2l6ZT0iMTIiPjIwMTAvMDYvMjQ8L3N0eWxlPjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+
QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpbWFsYXJpYWxzLypwaGFybWFjb2xvZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+QXRvdmFxdW9uZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+
RWxlY3Ryb24gVHJhbnNwb3J0IENvbXBsZXggSUlJLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0
b3JzPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVscywgTW9sZWN1bGFyPC9rZXl3b3JkPjxrZXl3b3Jk
PlBsYXNtb2RpdW0gZmFsY2lwYXJ1bS8qZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5Qcm90
ZWluIENvbmZvcm1hdGlvbjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj48c3R5bGUg
ZmFjZT0ibm9ybWFsIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj4yMDEwPC9zdHlsZT48L3ll
YXI+PHB1Yi1kYXRlcz48ZGF0ZT48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJIZWx2ZXRpY2Ei
IHNpemU9IjEyIj5BdWc8L3N0eWxlPjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjxz
dHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZldGljYSIgc2l6ZT0iMTIiPjE4NzktMDQwMiAo
RWxlY3Ryb25pYykmI3hEOzEzNjctNTkzMSAoTGlua2luZyk8L3N0eWxlPjwvaXNibj48YWNjZXNz
aW9uLW51bT48c3R5bGUgZmFjZT0ibm9ybWFsIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj4y
MDU3MDU1MDwvc3R5bGU+PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD48
c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj5odHRwOi8v
d3d3Lm5jYmkubmxtLm5paC5nb3YvZW50cmV6L3F1ZXJ5LmZjZ2k/Y21kPVJldHJpZXZlJmFtcDtk
Yj1QdWJNZWQmYW1wO2RvcHQ9Q2l0YXRpb24mYW1wO2xpc3RfdWlkcz0yMDU3MDU1MDwvc3R5bGU+
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT48c3R5
bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj5TMTM2Ny01OTMx
KDEwKTAwMDY4LTIgW3BpaV08L3N0eWxlPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9IkhlbHZl
dGljYSIgc2l6ZT0iMTIiPiYjeEQ7PC9zdHlsZT48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250
PSJIZWx2ZXRpY2EiIHNpemU9IjEyIj4xMC4xMDE2L2ouY2JwYS4yMDEwLjA1LjAwNTwvc3R5bGU+
PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48bGFuZ3VhZ2U+PHN0eWxlIGZhY2U9Im5vcm1hbCIg
Zm9udD0iSGVsdmV0aWNhIiBzaXplPSIxMiI+ZW5nPC9zdHlsZT48L2xhbmd1YWdlPjwvcmVjb3Jk
PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJ1cmdlc3M8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
ZWNOdW0+MjQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjI0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnNyYXc5d3hzNTVyNTVlcjU1MHBmMnZtZDVk
ZHh3ZHBmMnZ4Ij4yNDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFs
IEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnVy
Z2VzcywgUy4gSi48L2F1dGhvcj48YXV0aG9yPkFuZHJld3MsIFMuIFMuPC9hdXRob3I+PGF1dGhv
cj5TZWx6ZXIsIEEuPC9hdXRob3I+PGF1dGhvcj5LZWxseSwgSi4gWC48L2F1dGhvcj48YXV0aG9y
PlJpc2NvZSwgTS48L2F1dGhvcj48YXV0aG9yPlBleXRvbiwgRC4gSC48L2F1dGhvcj48L2F1dGhv
cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Qb3J0bGFuZCBTdGF0ZSBVbml2LCBQb3J0
bGFuZCwgT1IgOTcyMDcgVVNBJiN4RDtQb3J0bGFuZCBWQSBNZWQgQ3RyLCBQb3J0bGFuZCwgT1Ig
VVNBPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RGlwaGVueWxhbWluby1tb2RpZmllZCBD
aGxvcm9xdWluZXMgdGhhdCBhcmUgZWZmZWN0aXZlIGFnYWluc3QgQ2hsb3JvcXVpbmUgcmVzaXN0
YW50IG1hbGFyaWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW1lcmljYW4gSm91cm5hbCBvZiBU
cm9waWNhbCBNZWRpY2luZSBhbmQgSHlnaWVuZTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+
QW0gSiBUcm9wIE1lZCBIeWc8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5BbWVyaWNhbiBKb3VybmFsIG9mIFRyb3BpY2FsIE1lZGljaW5lIGFuZCBIeWdpZW5lPC9m
dWxsLXRpdGxlPjxhYmJyLTE+QW0gSiBUcm9wIE1lZCBIeWc8L2FiYnItMT48L3BlcmlvZGljYWw+
PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtZXJpY2FuIEpvdXJuYWwgb2YgVHJvcGljYWwg
TWVkaWNpbmUgYW5kIEh5Z2llbmU8L2Z1bGwtdGl0bGU+PGFiYnItMT5BbSBKIFRyb3AgTWVkIEh5
ZzwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjExMy0xMTM8L3BhZ2VzPjx2b2x1bWU+
NzM8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48ZGF0ZXM+PHllYXI+MjAwNTwveWVhcj48cHVi
LWRhdGVzPjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDItOTYz
NzwvaXNibj48YWNjZXNzaW9uLW51bT5JU0k6MDAwMjAyOTkwMDAwMzQwPC9hY2Nlc3Npb24tbnVt
Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD4mbHQ7R28gdG8gSVNJJmd0OzovLzAwMDIwMjk5MDAw
MDM0MDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48bGFuZ3VhZ2U+RW5nbGlzaDwvbGFuZ3Vh
Z2U+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGV5dG9uPC9BdXRob3I+PFllYXI+MjAw
NTwvWWVhcj48UmVjTnVtPjI1PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4yNTwvcmVjLW51
bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1
NTBwZjJ2bWQ1ZGR4d2RwZjJ2eCI+MjU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt
ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48
YXV0aG9yPlBleXRvbiwgRC4gSC48L2F1dGhvcj48YXV0aG9yPkJ1cmdlc3MsIFMuIEouPC9hdXRo
b3I+PGF1dGhvcj5BbmRyZXdzLCBTLjwvYXV0aG9yPjxhdXRob3I+TGllYm1hbiwgSy48L2F1dGhv
cj48YXV0aG9yPktlbGx5LCBKLiBYLjwvYXV0aG9yPjxhdXRob3I+UmlzY29lLCBNLjwvYXV0aG9y
PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlBvcnRsYW5kIFN0YXRlIFVu
aXYsIFBvcnRsYW5kLCBPUiA5NzIwNyBVU0EmI3hEO1BvcnRsYW5kIFZBIE1lZCBDdHIsIFBvcnRs
YW5kLCBPUiBVU0E8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5SZXZlcnNlZCBjaGxvcm9x
dWluZXM6IE1vbGVjdWxlcyBkZXNpZ25lZCB0byByZXZlcnNlIHRoZSByZXNpc3RhbmNlIHRvIENR
IGZvdW5kIGluIFBsYXNtb2RpdW0gZmFsY2lwYXJ1bSBtYWxhcmlhPC90aXRsZT48c2Vjb25kYXJ5
LXRpdGxlPkFtZXJpY2FuIEpvdXJuYWwgb2YgVHJvcGljYWwgTWVkaWNpbmUgYW5kIEh5Z2llbmU8
L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFtIEogVHJvcCBNZWQgSHlnPC9hbHQtdGl0bGU+
PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW1lcmljYW4gSm91cm5hbCBvZiBUcm9w
aWNhbCBNZWRpY2luZSBhbmQgSHlnaWVuZTwvZnVsbC10aXRsZT48YWJici0xPkFtIEogVHJvcCBN
ZWQgSHlnPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5B
bWVyaWNhbiBKb3VybmFsIG9mIFRyb3BpY2FsIE1lZGljaW5lIGFuZCBIeWdpZW5lPC9mdWxsLXRp
dGxlPjxhYmJyLTE+QW0gSiBUcm9wIE1lZCBIeWc8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxw
YWdlcz4zMS0zMTwvcGFnZXM+PHZvbHVtZT43Mzwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxk
YXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRh
dGVzPjwvZGF0ZXM+PGlzYm4+MDAwMi05NjM3PC9pc2JuPjxhY2Nlc3Npb24tbnVtPklTSTowMDAy
MDI5OTAwMDAwOTM8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPiZsdDtH
byB0byBJU0kmZ3Q7Oi8vMDAwMjAyOTkwMDAwMDkzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz
PjxsYW5ndWFnZT5FbmdsaXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv
cj5Dcm9zczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4yMjwvUmVjTnVtPjxyZWNv
cmQ+PHJlYy1udW1iZXI+MjI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSIyc3Jhdzl3eHM1NXI1NWVyNTUwcGYydm1kNWRkeHdkcGYydngiPjIyPC9rZXk+PC9m
b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl
Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Dcm9zcywgUi4gTS48L2F1dGhvcj48YXV0
aG9yPk5hbWVsaWtvbmRhLCBOLiBLLjwvYXV0aG9yPjxhdXRob3I+TXV0a2EsIFQuIFMuPC9hdXRo
b3I+PGF1dGhvcj5MdW9uZywgTC48L2F1dGhvcj48YXV0aG9yPkt5bGUsIEQuIEUuPC9hdXRob3I+
PGF1dGhvcj5NYW5ldHNjaCwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1
dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENoZW1pc3RyeSwgVW5pdmVyc2l0eSBvZiBTb3V0aCBG
bG9yaWRhLCBDSEUgMjA1LCA0MjAyIEUuIEZvd2xlciBBdmVudWUsIFRhbXBhLCBGbG9yaWRhIDMz
NjIwLCBVbml0ZWQgU3RhdGVzLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN5bnRoZXNp
cywgYW50aW1hbGFyaWFsIGFjdGl2aXR5LCBhbmQgc3RydWN0dXJlLWFjdGl2aXR5IHJlbGF0aW9u
c2hpcCBvZiA3LSgyLXBoZW5veHlldGhveHkpLTQoMUgpLXF1aW5vbG9uZXM8L3RpdGxlPjxzZWNv
bmRhcnktdGl0bGU+Sm91cm5hbCBvZiBtZWRpY2luYWwgY2hlbWlzdHJ5PC9zZWNvbmRhcnktdGl0
bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG1lZGljaW5hbCBjaGVtaXN0cnk8L2FsdC10aXRsZT48
L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Kb3VybmFsIG9mIE1lZGljaW5hbCBDaGVt
aXN0cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1lZCBDaGVtPC9hYmJyLTE+PC9wZXJpb2RpY2Fs
PjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Kb3VybmFsIG9mIE1lZGljaW5hbCBDaGVtaXN0
cnk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIE1lZCBDaGVtPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNh
bD48cGFnZXM+ODMyMS03PC9wYWdlcz48dm9sdW1lPjU0PC92b2x1bWU+PG51bWJlcj4yNDwvbnVt
YmVyPjxlZGl0aW9uPjIwMTEvMTEvMjU8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1h
bHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW1hbGFyaWFscy8qY2hlbWljYWwgc3ludGhlc2lzL2No
ZW1pc3RyeS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXRvdmFxdW9uZS9waGFybWFj
b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBMaW5lPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcg
UmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5NaWNlPC9rZXl3b3JkPjxrZXl3b3JkPlBsYXNt
b2RpdW0gZmFsY2lwYXJ1bS9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+UXVpbm9sb25l
cy8qY2hlbWljYWwgc3ludGhlc2lzL2NoZW1pc3RyeS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+U3RydWN0dXJlLUFjdGl2aXR5IFJlbGF0aW9uc2hpcDwva2V5d29yZD48L2tleXdvcmRz
PjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjIDIyPC9kYXRlPjwv
cHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMC00ODA0IChFbGVjdHJvbmljKSYjeEQ7MDAyMi0y
NjIzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yMjExMTkwNzwvYWNjZXNzaW9uLW51
bT48d29yay10eXBlPlJlc2VhcmNoIFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L3dvcmst
dHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292
L3B1Ym1lZC8yMjExMTkwNzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1y
ZXNvdXJjZS1udW0+MTAuMTAyMS9qbTIwMDcxOG08L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxs
YW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNyb3Nz
PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVjTnVtPjIyPC9SZWNOdW0+PHJlY29yZD48cmVj
LW51bWJlcj4yMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9
IjJzcmF3OXd4czU1cjU1ZXI1NTBwZjJ2bWQ1ZGR4d2RwZjJ2eCI+MjI8L2tleT48L2ZvcmVpZ24t
a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy
aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNyb3NzLCBSLiBNLjwvYXV0aG9yPjxhdXRob3I+TmFt
ZWxpa29uZGEsIE4uIEsuPC9hdXRob3I+PGF1dGhvcj5NdXRrYSwgVC4gUy48L2F1dGhvcj48YXV0
aG9yPkx1b25nLCBMLjwvYXV0aG9yPjxhdXRob3I+S3lsZSwgRC4gRS48L2F1dGhvcj48YXV0aG9y
Pk1hbmV0c2NoLCBSLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy
ZXNzPkRlcGFydG1lbnQgb2YgQ2hlbWlzdHJ5LCBVbml2ZXJzaXR5IG9mIFNvdXRoIEZsb3JpZGEs
IENIRSAyMDUsIDQyMDIgRS4gRm93bGVyIEF2ZW51ZSwgVGFtcGEsIEZsb3JpZGEgMzM2MjAsIFVu
aXRlZCBTdGF0ZXMuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U3ludGhlc2lzLCBhbnRp
bWFsYXJpYWwgYWN0aXZpdHksIGFuZCBzdHJ1Y3R1cmUtYWN0aXZpdHkgcmVsYXRpb25zaGlwIG9m
IDctKDItcGhlbm94eWV0aG94eSktNCgxSCktcXVpbm9sb25lczwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5Kb3VybmFsIG9mIG1lZGljaW5hbCBjaGVtaXN0cnk8L3NlY29uZGFyeS10aXRsZT48YWx0
LXRpdGxlPkpvdXJuYWwgb2YgbWVkaWNpbmFsIGNoZW1pc3RyeTwvYWx0LXRpdGxlPjwvdGl0bGVz
PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpvdXJuYWwgb2YgTWVkaWNpbmFsIENoZW1pc3RyeTwv
ZnVsbC10aXRsZT48YWJici0xPkogTWVkIENoZW08L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1w
ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpvdXJuYWwgb2YgTWVkaWNpbmFsIENoZW1pc3RyeTwvZnVs
bC10aXRsZT48YWJici0xPkogTWVkIENoZW08L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl
cz44MzIxLTc8L3BhZ2VzPjx2b2x1bWU+NTQ8L3ZvbHVtZT48bnVtYmVyPjI0PC9udW1iZXI+PGVk
aXRpb24+MjAxMS8xMS8yNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5
d29yZD48a2V5d29yZD5BbnRpbWFsYXJpYWxzLypjaGVtaWNhbCBzeW50aGVzaXMvY2hlbWlzdHJ5
L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5BdG92YXF1b25lL3BoYXJtYWNvbG9neTwv
a2V5d29yZD48a2V5d29yZD5DZWxsIExpbmU8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBSZXNpc3Rh
bmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+UGxhc21vZGl1bSBm
YWxjaXBhcnVtL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5RdWlub2xvbmVzLypjaGVt
aWNhbCBzeW50aGVzaXMvY2hlbWlzdHJ5L3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5T
dHJ1Y3R1cmUtQWN0aXZpdHkgUmVsYXRpb25zaGlwPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz
Pjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWMgMjI8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4xNTIwLTQ4MDQgKEVsZWN0cm9uaWMpJiN4RDswMDIyLTI2MjMgKExp
bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIyMTExOTA3PC9hY2Nlc3Npb24tbnVtPjx3b3Jr
LXR5cGU+UmVzZWFyY2ggU3VwcG9ydCwgTm9uLVUuUy4gR292JmFwb3M7dDwvd29yay10eXBlPjx1
cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk
LzIyMTExOTA3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl
LW51bT4xMC4xMDIxL2ptMjAwNzE4bTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PGxhbmd1YWdl
PmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 25-30PharmacodynamicsMode of Action. Atovaquone is a competitive inhibitor of ubiquinol, specifically inhibiting the mitochondrial electron transport chain at the bc1 complex. ADDIN EN.CITE <EndNote><Cite><Author>Fry</Author><Year>1992</Year><RecNum>5615</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>5615</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">5615</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fry, M.</author><author>Pudney, M.</author></authors></contributors><titles><title>Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4- (4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80)</title><secondary-title>Biochem Pharmacol</secondary-title></titles><periodical><full-title>Biochemical pharmacology</full-title><abbr-1>Biochem Pharmacol</abbr-1></periodical><pages>1545-53</pages><volume>43</volume><number>7</number><keywords><keyword>Animal</keyword><keyword>Antimalarials/*pharmacology</keyword><keyword>Binding Sites</keyword><keyword>Comparative Study</keyword><keyword>Liver/drug effects/enzymology</keyword><keyword>Mitochondria/drug effects/enzymology</keyword><keyword>Naphthoquinones/*pharmacology</keyword><keyword>NADH Dehydrogenase/antagonists & inhibitors</keyword><keyword>Plasmodium falciparum/*drug effects/enzymology</keyword><keyword>Rats</keyword><keyword>Ubiquinol-Cytochrome-c Reductase/antagonists & inhibitors/*metabolism</keyword></keywords><dates><year>1992</year></dates><label>92232011</label><urls></urls></record></Cite></EndNote>31 Inhibition of bc1 activity results in a loss of mitochondrial function.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tcml2YXN0YXZhPC9BdXRob3I+PFllYXI+MTk5NzwvWWVh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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tcml2YXN0YXZhPC9BdXRob3I+PFllYXI+MTk5NzwvWWVh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==
ADDIN EN.CITE.DATA 32, 33 During the intra-erythrocytic stage of infection, a key role of the parasite mitochondrion is to provide orotate for pyrimidine biosynthesis through the activity of dihydroorotate dehydrogenase (DHODH). Consistent with this, inhibition of the bc1 complex by atovaquone affects the concentrations of metabolites in the pyrimidine biosynthetic pathway.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXltb3VyPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXltb3VyPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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ADDIN EN.CITE.DATA 34, 35 Indeed, transgenic P. falciparum parasites expressing ubiquinone-independent yeast DHODH have been shown to display an atovaquone-resistant phenotype. ADDIN EN.CITE <EndNote><Cite><Author>Painter</Author><Year>2007</Year><RecNum>17744</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>17744</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">17744</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Painter, H. J.</author><author>Morrisey, J. M.</author><author>Mather, M. W.</author><author>Vaidya, A. B.</author></authors></contributors><auth-address>Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.</auth-address><titles><title>Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><pages>88-91</pages><volume>446</volume><number>7131</number><dates><year>2007</year><pub-dates><date>Mar 1</date></pub-dates></dates><accession-num>17330044</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>36 In addition, a recent study suggests that a further cellular consequence of mitochondrial inhibition by atovaquone is the inhibition of purine biosynthesis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWx1c3U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWx1c3U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 37 Blood stage parasite death as a result of atovaquone is relatively slow compared to other antimalarials such as artemisinin and chloroquine.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl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ADDIN EN.CITE.DATA 25, 38 This feature appears to be consistent with other mitochondrial-acting antimalarials and is possibly due to the drug acting only on late trophozoites and not on the earlier “ring” stages.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFnaW5pPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWFnaW5pPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48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ADDIN EN.CITE.DATA 25 Atovaquone is however active against liver stages, resulting in its utility as a prophylaxis drug, however it is not believed to be active against “dormant” hypnozoites.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWxsb288L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWxsb288L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 8, 39Mechanism of Parasite Resistance to Atovaquone/MalaroneTM. Although the crystal structure of the P. falciparum cytochrome bc1 complex is not available, details of atovaquone binding to cytochrome b have been elucidated based on studies performed on model organisms and molecular modelling. These studies, that include Electron Paramagnetic Resonance spectroscopy of the Rieske [2Fe-2S] cluster, site-directed mutagenesis of model organism cytochrome b, and gene sequencing of atovaquone-resistant Plasmodium species, demonstrate that atovaquone is most likely a competitive inhibitor of the parasite's cytochrome b quinol oxidation (Qo) site (Figure 3).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXNzbDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXNzbDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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ADDIN EN.CITE.DATA 28, 40MalaroneTM drug failure has been associated with a mis-sense point mutation at position 268 in cytochrome b, exchanging tyrosine for serine (Y268S) or, less frequently, asparagine (Y268N).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3JzaW5jemt5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3JzaW5jemt5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVh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ADDIN EN.CITE.DATA 41-45 Position 268 in cytochrome b is highly conserved across all phyla and is located within the “ef” helix component of the Qo site which is putatively involved in ubiquinol binding. The resultant atovaquone-resistant growth IC50 phenotype of these mutants is some 1000-fold higher than susceptible strains, however this is accompanied by a ~40 % reduction in the Vmax of the bc1 complex, suggestive of a significant fitness cost to the parasite.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXNoZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXNoZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 46It is well documented that atovaquone monotherapy gives rise to de novo resistance very rapidly.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGlvZGluaTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGlvZGluaTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+
PFJlY051bT4zMDA5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw
dCI+NDcsIDQ4PC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzAwOTwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9Inhzcno5cHIwdDVz
OTJ3ZWZ2emh4eHR0Y3ZlYTJ6eGZwMHZmciI+MzAwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt
dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh
dXRob3JzPjxhdXRob3I+Q2hpb2RpbmksIFAuIEwuPC9hdXRob3I+PGF1dGhvcj5Db25sb24sIEMu
IFAuPC9hdXRob3I+PGF1dGhvcj5IdXRjaGluc29uLCBELiBCLjwvYXV0aG9yPjxhdXRob3I+RmFy
cXVoYXIsIEouIEEuPC9hdXRob3I+PGF1dGhvcj5IYWxsLCBBLiBQLjwvYXV0aG9yPjxhdXRob3I+
UGV0bywgVC4gRS48L2F1dGhvcj48YXV0aG9yPkJpcmxleSwgSC48L2F1dGhvcj48YXV0aG9yPldh
cnJlbGwsIEQuIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp
dGxlPkV2YWx1YXRpb24gb2YgYXRvdmFxdW9uZSBpbiB0aGUgdHJlYXRtZW50IG9mIHBhdGllbnRz
IHdpdGggdW5jb21wbGljYXRlZCBQbGFzbW9kaXVtIGZhbGNpcGFydW0gbWFsYXJpYTwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5KIEFudGltaWNyb2IgQ2hlbW90aGVyPC9zZWNvbmRhcnktdGl0bGU+
PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+VGhlIEpvdXJuYWwgb2YgYW50aW1pY3Jv
YmlhbCBjaGVtb3RoZXJhcHk8L2Z1bGwtdGl0bGU+PGFiYnItMT5KIEFudGltaWNyb2IgQ2hlbW90
aGVyPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDczLTg8L3BhZ2VzPjx2b2x1bWU+MzY8
L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdv
cmQ+PGtleXdvcmQ+QW50aW1hbGFyaWFscy9hZHZlcnNlIGVmZmVjdHMvYmxvb2QvKnRoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Eb3NlLVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1
Zzwva2V5d29yZD48a2V5d29yZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPkV2YWx1YXRpb24gU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5IdW1hbjwva2V5
d29yZD48a2V5d29yZD5NYWxhcmlhLCBGYWxjaXBhcnVtL2Jsb29kLypkcnVnIHRoZXJhcHk8L2tl
eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlPC9rZXl3b3Jk
PjxrZXl3b3JkPk5hcGh0aG9xdWlub25lcy9hZHZlcnNlIGVmZmVjdHMvYmxvb2QvKnRoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk1PC95ZWFyPjwvZGF0ZXM+PGxhYmVsPjk2NDE4ODI0PC9s
YWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TG9vYXJlZXN1
d2FuPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVjTnVtPjQzPC9SZWNOdW0+PHJlY29yZD48
cmVjLW51bWJlcj40MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt
aWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBwZjJ2bWQ1ZGR4d2RwZjJ2eCI+NDM8L2tleT48L2ZvcmVp
Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv
bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkxvb2FyZWVzdXdhbiwgUy48L2F1dGhvcj48YXV0
aG9yPlZpcmF2YW4sIEMuPC9hdXRob3I+PGF1dGhvcj5XZWJzdGVyLCBILiBLLjwvYXV0aG9yPjxh
dXRob3I+S3lsZSwgRC4gRS48L2F1dGhvcj48YXV0aG9yPkh1dGNoaW5zb24sIEQuIEIuPC9hdXRo
b3I+PGF1dGhvcj5DYW5maWVsZCwgQy4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIENsaW5pY2FsIFRyb3BpY2FsIE1lZGljaW5l
LCBGYWN1bHR5IG9mIFRyb3BpY2FsIE1lZGljaW5lLCBNYWhpZG9sIFVuaXZlcnNpdHksIEJhbmdr
b2ssIFRoYWlsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2FsIHN0dWRp
ZXMgb2YgYXRvdmFxdW9uZSwgYWxvbmUgb3IgaW4gY29tYmluYXRpb24gd2l0aCBvdGhlciBhbnRp
bWFsYXJpYWwgZHJ1Z3MsIGZvciB0cmVhdG1lbnQgb2YgYWN1dGUgdW5jb21wbGljYXRlZCBtYWxh
cmlhIGluIFRoYWlsYW5kPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogVHJvcCBNZWQgSHln
PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW1lcmlj
YW4gSm91cm5hbCBvZiBUcm9waWNhbCBNZWRpY2luZSBhbmQgSHlnaWVuZTwvZnVsbC10aXRsZT48
YWJici0xPkFtIEogVHJvcCBNZWQgSHlnPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz42Mi02
PC9wYWdlcz48dm9sdW1lPjU0PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MTk5
Ni8wMS8wMTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWN1dGUgRGlzZWFzZTwva2V5d29y
ZD48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW1hbGFyaWFscy8qdGhlcmFwZXV0aWMg
dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkF0b3ZhcXVvbmU8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBU
aGVyYXB5LCBDb21iaW5hdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGFyaWEsIEZhbGNpcGFydW0vKmRydWcg
dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBB
Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5hcGh0aG9xdWlub25lcy9hZG1pbmlzdHJhdGlvbiAmYW1w
OyBkb3NhZ2UvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh
cj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0
ZXM+PGlzYm4+MDAwMi05NjM3IChQcmludCkmI3hEOzAwMDItOTYzNyAoTGlua2luZyk8L2lzYm4+
PGFjY2Vzc2lvbi1udW0+ODY1MTM3MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxz
Pjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L2VudHJlei9xdWVyeS5mY2dpP2NtZD1S
ZXRyaWV2ZSZhbXA7ZGI9UHViTWVkJmFtcDtkb3B0PUNpdGF0aW9uJmFtcDtsaXN0X3VpZHM9ODY1
MTM3MjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48
L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE.DATA 47, 48 However, the underlying reason for this phenomenon has not been determined and, as discussed in the next section, may be partially explained by pharmacodynamics/pharmacokinetic pharmacokinetic considerations (related to the physicochemical properties of atovaquone combined with a slow rate of sterilization) as well as hitherto untested considerations related to the molecular target such as for example the effect of an increased mutation rate of mitochondrially-encoded genes such as cytochrome b compared to nuclear encoded genes. ADDIN EN.CITE <EndNote><Cite><Author>Pesole</Author><Year>1999</Year><RecNum>17857</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>17857</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">17857</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesole, G.</author><author>Gissi, C.</author><author>De Chirico, A.</author><author>Saccone, C.</author></authors></contributors><auth-address>Dipartimento di Fisiologia e Biochimica Generali, Universita di Milano, via Celoria 26, 20133 Milano, Italy. graziano.pesole@unimi.it</auth-address><titles><title>Nucleotide substitution rate of mammalian mitochondrial genomes</title><secondary-title>J Mol Evol</secondary-title></titles><pages>427-34</pages><volume>48</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>DNA, Mitochondrial/*genetics</keyword><keyword>Evolution, Molecular</keyword><keyword>*Genome</keyword><keyword>Humans</keyword><keyword>Mammals/*genetics</keyword><keyword>*Mutation</keyword><keyword>RNA, Ribosomal/genetics</keyword><keyword>RNA, Transfer/genetics</keyword></keywords><dates><year>1999</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>10079281</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>49 Furthermore, it has been reported that an in vitro atovaquone resistant parasite line has been generated in the laboratory possessing wild-type cyt b.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWlsa3N0ZWluPC9BdXRob3I+PFllYXI+MjAwODwvWWVh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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWlsa3N0ZWluPC9BdXRob3I+PFllYXI+MjAwODwvWWVh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==
ADDIN EN.CITE.DATA 50 The mechanism underpinning the parasite’s atovaquone resistant phenotype in this strain remains to be elucidated.The speed of development of resistance to a new antimalarial is an important consideration. According to the Medicines for Malaria Venture (MMV) target product profiles (TPPs), pre-clinical development of new bc1-acting antimalarials must show activity against a panel of multi-drug antimalarial parasites that include atovaquone resistant isolates. There are also in vitro speed of development of resistance assays that are available that can be used to guide go/no-go development decisions. ADDIN EN.CITE <EndNote><Cite><Author>Ding</Author><Year>2012</Year><RecNum>18743</RecNum><DisplayText><style face="superscript">51</style></DisplayText><record><rec-number>18743</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">18743</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ding, X. C.</author><author>Ubben, D.</author><author>Wells, T. N.</author></authors></contributors><auth-address>Medicines for Malaria Venture, 20 rte de Pre Bois, Geneva, CH 1215, Switzerland. dingx@.</auth-address><titles><title>A framework for assessing the risk of resistance for anti-malarials in development</title><secondary-title>Malaria journal</secondary-title><alt-title>Malaria journal</alt-title></titles><periodical><full-title>Malaria journal</full-title><abbr-1>Malar J</abbr-1></periodical><alt-periodical><full-title>Malaria journal</full-title><abbr-1>Malar J</abbr-1></alt-periodical><pages>292</pages><volume>11</volume><edition>2012/08/24</edition><dates><year>2012</year></dates><isbn>1475-2875 (Electronic)
1475-2875 (Linking)</isbn><accession-num>22913649</accession-num><urls><related-urls><url> Whether the observed rapid on-set of de novo resistance seen in atovaquone is based on the physicochemical property of the molecule, or whether it is based on inherent issues relating to the biological target, it is likely that new bc1-target antimalarials will require to be married with a partner drug, unless the candidate drugs possess biologically distinct polypharmacology. PharmacokineticsThe pharmacokinetic parameters of atovaquone in the currently utilised formulation (Malarone?, 250 mg atovaquone + 100 mg proguanil) have been determined (Figure 4).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
ZWNOdW0+NDY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41
Mjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ2PC9yZWMtbnVtYmVy
Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iMnNyYXc5d3hzNTVyNTVlcjU1MHBm
MnZtZDVkZHh3ZHBmMnZ4Ij40Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK
b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo
b3I+VGhhcGFyLCBNLiBNLjwvYXV0aG9yPjxhdXRob3I+QXNodG9uLCBNLjwvYXV0aG9yPjxhdXRo
b3I+TGluZGVnYXJkaCwgTi48L2F1dGhvcj48YXV0aG9yPkJlcmdxdmlzdCwgWS48L2F1dGhvcj48
YXV0aG9yPk5pdmVsaXVzLCBTLjwvYXV0aG9yPjxhdXRob3I+Sm9oYW5zc29uLCBJLjwvYXV0aG9y
PjxhdXRob3I+QmpvcmttYW4sIEEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh
dXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBNYWxhcmlhIFJl
c2VhcmNoIExhYm9yYXRvcnksIEw3LzAzLCBLYXJvbGluc2thIEhvc3BpdGFsLCBTdG9ja2hvbG0g
MTcxNzYsIFN3ZWRlbi4gbWl0bWFpQGtzLnNlPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+
VGltZS1kZXBlbmRlbnQgcGhhcm1hY29raW5ldGljcyBhbmQgZHJ1ZyBtZXRhYm9saXNtIG9mIGF0
b3ZhcXVvbmUgcGx1cyBwcm9ndWFuaWwgKE1hbGFyb25lKSB3aGVuIHRha2VuIGFzIGNoZW1vcHJv
cGh5bGF4aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RXVyIEogQ2xpbiBQaGFybWFjb2w8L3Nl
Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkV1cm9wZWFuIGpvdXJuYWwgb2YgY2xpbmljYWwgcGhh
cm1hY29sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+RXVy
IEogQ2xpbiBQaGFybWFjb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5FdXJvcGVhbiBqb3VybmFsIG9m
IGNsaW5pY2FsIHBoYXJtYWNvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGlj
YWw+PGZ1bGwtdGl0bGU+RXVyIEogQ2xpbiBQaGFybWFjb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5F
dXJvcGVhbiBqb3VybmFsIG9mIGNsaW5pY2FsIHBoYXJtYWNvbG9neTwvYWJici0xPjwvYWx0LXBl
cmlvZGljYWw+PHBhZ2VzPjE5LTI3PC9wYWdlcz48dm9sdW1lPjU4PC92b2x1bWU+PG51bWJlcj4x
PC9udW1iZXI+PGVkaXRpb24+MjAwMi8wNC8xNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+
QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aW1hbGFyaWFscy9hZHZlcnNlIGVmZmVjdHMvYmxv
b2QvKnBoYXJtYWNva2luZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QXRvdmFxdW9uZTwva2V5d29y
ZD48a2V5d29yZD5CaW9sb2dpY2FsIEF2YWlsYWJpbGl0eTwva2V5d29yZD48a2V5d29yZD5Eb3Nl
LVJlc3BvbnNlIFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5EcnVnIENvbWJp
bmF0aW9uczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R2Vub3R5
cGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdv
cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmFwaHRob3F1aW5vbmVz
L2FkdmVyc2UgZWZmZWN0cy9ibG9vZC8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29y
ZD5QaGVub3R5cGU8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ3VhbmlsL2FkdmVyc2UgZWZmZWN0cy9i
bG9vZC8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tl
eXdvcmQ+PGtleXdvcmQ+VHJpYXppbmVzL2FkdmVyc2UgZWZmZWN0cy9ibG9vZC8qcGhhcm1hY29r
aW5ldGljczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWIt
ZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAzMS02OTcw
IChQcmludCkmI3hEOzAwMzEtNjk3MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTE5
NTY2Njk8L2FjY2Vzc2lvbi1udW0+PHdvcmstdHlwZT5DbGluaWNhbCBUcmlhbCYjeEQ7SW4gVml0
cm88L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5s
bS5uaWguZ292L3B1Ym1lZC8xMTk1NjY2OTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxl
Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDAyMjgtMDAyLTA0MjYtOTwvZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwv
RW5kTm90ZT4A
ADDIN EN.CITE.DATA 52 Median atovaquone plasma AUC (h.?M), t1/2 (h), Cmax (?M) and tmax (h) were 295, 87.2, 3.74, 3.25, respectively, following single-dose and 254, 55.9, 13.8 and 4.00, respectively, upon reaching steady-state. The similar AUC values observed between single-dose and steady-state dosing suggests no unexpected accumulation of atovaquone following repeated administration, although this may be due to saturation of plasma atovaquone concentrations and an increase in atovaquone concentrations in tissues cannot be ruled out. Atovaquone IC50 against susceptible malaria in vitro is very low, ranging from 1 to ~3.5 nM. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaG9zaXRuaXRoaWt1bDwvQXV0aG9yPjxZZWFyPjIwMDg8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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaG9zaXRuaXRoaWt1bDwvQXV0aG9yPjxZZWFyPjIwMDg8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ADDIN EN.CITE.DATA 31, 53, 54 This has resulted in the belief that atovaquone plasma concentrations (around 1-10 ?M, see Figure 4) are sufficient to produce total suppression of malaria. However, atovaquone shows extremely high levels of plasma protein binding (>99.5%) and therefore the concentration of un-bound atovaquone is likely to be significantly lower.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA 55 Extrapolations of Pharmacokinetic-Pharmacodynamic dynamics using in vitro data should therefore be treated with caution.At present, there are no established minimum effective plasma concentrations of atovaquone for malaria prophylaxis. However, a clear correlation between atovaquone steady-state plasma concentration and treatment success has been established in Pneumocystis pneumonia in patients with AIDS.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA 56 Atovaquone plasma concentrations of 10 to <15 ?g / mL and 15 to <20 ?g / mL resulted in 79% and 95% treatment success, respectively. Furthermore, there have been case reports of atovaquone treatment failure in antimalarial therapy that were not explained by drug resistance mutations, and patients with body weight >100 kg have a marked increased chance of treatment failure compared to <100 kg patients, both of which suggest drug concentration may be a factor in determining treatment failure.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWNobWFubjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWNobWFubjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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ADDIN EN.CITE.DATA 42, 57, 58 The prediction of atovaquone therapy failure and resistance selection using drug concentration parameters has the potential to improve current patient therapy and an investigation determining a PK-PD relationship is warranted.Absorption. Absorption of atovaquone shows dose-limitation, with maximum absorption observed using 750 mg tablets.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 59 Poor drug solubility was suggested as the cause of this limit to absorption, and this led to the development of an atovaquone liquid suspension formulation, which showed improved Pneumocystis pneumonia treatment success compared to the tablet formation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy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 EN.CITE.DATA 60The bioavailability of 750 mg atovaquone when taken with food was 23% in HIV-infected patients. ADDIN EN.CITE <EndNote><Cite><Author>Hussein</Author><Year>1997</Year><RecNum>2029</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>2029</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">2029</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hussein, Z.</author><author>Eaves, J.</author><author>Hutchinson, D. B.</author><author>Canfield, C. J.</author></authors></contributors><titles><title>Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum</title><secondary-title>Clin Pharmacol Ther</secondary-title></titles><pages>518-30</pages><volume>61</volume><number>5</number><keywords><keyword>Adolescence</keyword><keyword>Adult</keyword><keyword>Analysis of Variance</keyword><keyword>Antimalarials/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Computer Simulation</keyword><keyword>Databases, Factual</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Gabon</keyword><keyword>Human</keyword><keyword>Kenya</keyword><keyword>Malaria, Falciparum/blood/*drug therapy/metabolism</keyword><keyword>Male</keyword><keyword>Middle Age</keyword><keyword>Models, Biological</keyword><keyword>Naphthoquinones/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Philippines</keyword><keyword>Support, Non-U.S. Gov't</keyword><keyword>Thailand</keyword><keyword>Zambia</keyword></keywords><dates><year>1997</year></dates><label>97307201</label><urls></urls></record></Cite></EndNote>61 Combining data from six clinical trials, the inter-patient variability of atovaquone bioavailability is substantial and has been determined at 107%, which is likely due to the drug’s low solubility and the effects of food.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXNzZWluPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXNzZWluPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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 EN.CITE.DATA 61-63The oral absorption of atovaquone increased when taken with a high fat meal (2 slices of toast with 56 g butter, with 3.9-fold exposure compared to fasted), whereas a minimal-fat meal (2 slices of toast) had minimal impact on absorption.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA 63 Consequently, it is recommended that atovaquone be taken with a high-fat meal. However, a recent in vitro study showed that atovaquone IC50 increased 20-fold when serum used in the assay was taken from a subject recently given a high-fat meal, compared to serum from a fasted subject (0.5 ng / mL to 12 ng / mL, p < 0.01). ADDIN EN.CITE <EndNote><Cite><Author>Chotivanich</Author><Year>2012</Year><RecNum>58</RecNum><DisplayText><style face="superscript">64</style></DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chotivanich, K.</author><author>Mungthin, M.</author><author>Ruengweerayuth, R.</author><author>Udomsangpetch, R.</author><author>Dondorp, A. M.</author><author>Singhasivanon, P.</author><author>Pukrittayakamee, S.</author><author>White, N. J.</author></authors></contributors><titles><title>The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against plasmodium falciparum</title><secondary-title>Malar J</secondary-title><alt-title>Malaria journal</alt-title></titles><periodical><full-title>Malar J</full-title></periodical><pages>177</pages><volume>11</volume><number>1</number><edition>2012/05/30</edition><dates><year>2012</year><pub-dates><date>May 28</date></pub-dates></dates><isbn>1475-2875 (Electronic)
1475-2875 (Linking)</isbn><accession-num>22640826</accession-num><urls><related-urls><url> A correlation between high serum triglyceride concentrations and high atovaquone IC50 was observed, suggesting reduced free (unbound) atovaquone concentrations due to increased drug-fat binding. The clinical relevance of this finding is unknown, but the impact to atovaquone PK is likely to be transient and is unlikely to outweigh the benefit of increased atovaquone absorption.Dissolution of atovaquone tablets increases in the presence of milk, and therefore the presence of milk in meals may increase atovaquone bioavailability in patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNvbGFpZGVzPC9BdXRob3I+PFllYXI+MTk5OTwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNvbGFpZGVzPC9BdXRob3I+PFllYXI+MTk5OTwvWWVh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ADDIN EN.CITE.DATA 62 This may provide an alternative strategy to high-fat meals when aiming to maximise the bioavailability of atovaquone, although this has not been shown clinically.Distribution. Atovaquone is highly bound to plasma protein (>99.5%) and shows high affinity for human serum albumin, although the low drug clearance rate suggests that atovaquone may also accumulate in tissues, where it is protected from biliary clearance.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA 55 In a study of atovaquone population pharmacokinetics, the volume of distribution of atovaquone was 7.98 L / kg, although individual values were markedly linked to body weight; volume of distribution shows a linear increase with increased patient body weight. ADDIN EN.CITE <EndNote><Cite><Author>Hussein</Author><Year>1997</Year><RecNum>2029</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>2029</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">2029</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hussein, Z.</author><author>Eaves, J.</author><author>Hutchinson, D. B.</author><author>Canfield, C. J.</author></authors></contributors><titles><title>Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum</title><secondary-title>Clin Pharmacol Ther</secondary-title></titles><pages>518-30</pages><volume>61</volume><number>5</number><keywords><keyword>Adolescence</keyword><keyword>Adult</keyword><keyword>Analysis of Variance</keyword><keyword>Antimalarials/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Computer Simulation</keyword><keyword>Databases, Factual</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Gabon</keyword><keyword>Human</keyword><keyword>Kenya</keyword><keyword>Malaria, Falciparum/blood/*drug therapy/metabolism</keyword><keyword>Male</keyword><keyword>Middle Age</keyword><keyword>Models, Biological</keyword><keyword>Naphthoquinones/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Philippines</keyword><keyword>Support, Non-U.S. Gov't</keyword><keyword>Thailand</keyword><keyword>Zambia</keyword></keywords><dates><year>1997</year></dates><label>97307201</label><urls></urls></record></Cite></EndNote>61Metabolism. Under normal conditions, there is no evidence that atovaquone is significantly metabolised in humans, or that metabolism is required for drug elimination. It may be possible that certain enzymes could be induced and therefore lead to increased atovaquone biotransformation, but this has not been demonstrated.Elimination. Atovaquone pharmacokinetics is characterised by an extremely long elimination half life of around 50 to 84 hours.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl
Y051bT41NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjU5
LCA2MywgNjU8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj41NzwvcmVj
LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1
ZXI1NTBwZjJ2bWQ1ZGR4d2RwZjJ2eCI+NTc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg
bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y
cz48YXV0aG9yPlJvbGFuLCBQLiBFLjwvYXV0aG9yPjxhdXRob3I+TWVyY2VyLCBBLiBKLjwvYXV0
aG9yPjxhdXRob3I+V2VhdGhlcmxleSwgQi4gQy48L2F1dGhvcj48YXV0aG9yPkhvbGRpY2gsIFQu
PC9hdXRob3I+PGF1dGhvcj5NZWlyZSwgSC48L2F1dGhvcj48YXV0aG9yPlBlY2ssIFIuIFcuPC9h
dXRob3I+PGF1dGhvcj5SaWRvdXQsIEcuPC9hdXRob3I+PGF1dGhvcj5Qb3NuZXIsIEouPC9hdXRo
b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+V2VsbGNvbWUgUmVzZWFy
Y2ggTGFib3JhdG9yaWVzLCBCZWNrZW5oYW0sIEtlbnQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48
dGl0bGU+RXhhbWluYXRpb24gb2Ygc29tZSBmYWN0b3JzIHJlc3BvbnNpYmxlIGZvciBhIGZvb2Qt
aW5kdWNlZCBpbmNyZWFzZSBpbiBhYnNvcnB0aW9uIG9mIGF0b3ZhcXVvbmU8L3RpdGxlPjxzZWNv
bmRhcnktdGl0bGU+QnIgSiBDbGluIFBoYXJtYWNvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0
bGU+QnJpdGlzaCBqb3VybmFsIG9mIGNsaW5pY2FsIHBoYXJtYWNvbG9neTwvYWx0LXRpdGxlPjwv
dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJyIEogQ2xpbiBQaGFybWFjb2w8L2Z1bGwt
dGl0bGU+PGFiYnItMT5Ccml0aXNoIGpvdXJuYWwgb2YgY2xpbmljYWwgcGhhcm1hY29sb2d5PC9h
YmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CciBKIENsaW4g
UGhhcm1hY29sPC9mdWxsLXRpdGxlPjxhYmJyLTE+QnJpdGlzaCBqb3VybmFsIG9mIGNsaW5pY2Fs
IHBoYXJtYWNvbG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjEzLTIwPC9wYWdl
cz48dm9sdW1lPjM3PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MTk5NC8wMS8w
MTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QXRv
dmFxdW9uZTwva2V5d29yZD48a2V5d29yZD5DaHJvbWF0b2dyYXBoeSwgSGlnaCBQcmVzc3VyZSBM
aXF1aWQ8L2tleXdvcmQ+PGtleXdvcmQ+RGlldGFyeSBGYXRzLyphZG1pbmlzdHJhdGlvbiAmYW1w
OyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+RmFzdGluZzwva2V5d29yZD48a2V5d29yZD4qRm9v
ZDwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJ
bnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD4qSW50ZXN0aW5hbCBBYnNvcnB0aW9uL2RydWcg
ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBB
Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5hcGh0aG9xdWlub25lcy9hZG1pbmlzdHJhdGlvbiAmYW1w
OyBkb3NhZ2UvYmxvb2QvKnBoYXJtYWNva2luZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+U2luY2Fs
aWRlL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+U3VzcGVuc2lvbnM8L2tleXdvcmQ+PGtleXdvcmQ+VGFibGV0czwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SmFuPC9kYXRl
PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDMwNi01MjUxIChQcmludCkmI3hEOzAzMDYtNTI1
MSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+ODE0ODIxMzwvYWNjZXNzaW9uLW51bT48
d29yay10eXBlPkNsaW5pY2FsIFRyaWFsJiN4RDtSYW5kb21pemVkIENvbnRyb2xsZWQgVHJpYWw8
L3dvcmstdHlwZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5u
aWguZ292L3B1Ym1lZC84MTQ4MjEzPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20y
PjEzNjQ3MDM8L2N1c3RvbTI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRl
PjxDaXRlPjxBdXRob3I+SHVnaGVzPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48UmVjTnVtPjUz
PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj41MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBwZjJ2bWQ1ZGR4d2RwZjJ2
eCI+NTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl
Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkh1Z2hlcywgVy4g
VC48L2F1dGhvcj48YXV0aG9yPktlbm5lZHksIFcuPC9hdXRob3I+PGF1dGhvcj5TaGVuZXAsIEou
IEwuPC9hdXRob3I+PGF1dGhvcj5GbHlubiwgUC4gTS48L2F1dGhvcj48YXV0aG9yPkhldGhlcmlu
Z3RvbiwgUy4gVi48L2F1dGhvcj48YXV0aG9yPkZ1bGxlbiwgRy48L2F1dGhvcj48YXV0aG9yPkxh
bmNhc3RlciwgRC4gSi48L2F1dGhvcj48YXV0aG9yPlN0ZWluLCBELiBTLjwvYXV0aG9yPjxhdXRo
b3I+UGFsdGUsIFMuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbmJhdW0sIEQuPC9hdXRob3I+PGF1dGhv
cj5ldCBhbC4sPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+
RGVwYXJ0bWVudCBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzLCBTdC4gSnVkZSBDaGlsZHJlbiZhcG9z
O3MgUmVzZWFyY2ggSG9zcGl0YWwsIE1lbXBoaXMsIFROIDM4MTAxLTAzMTguPC9hdXRoLWFkZHJl
c3M+PHRpdGxlcz48dGl0bGU+U2FmZXR5IGFuZCBwaGFybWFjb2tpbmV0aWNzIG9mIDU2NkM4MCwg
YSBoeWRyb3h5bmFwaHRob3F1aW5vbmUgd2l0aCBhbnRpLVBuZXVtb2N5c3RpcyBjYXJpbmlpIGFj
dGl2aXR5OiBhIHBoYXNlIEkgc3R1ZHkgaW4gaHVtYW4gaW1tdW5vZGVmaWNpZW5jeSB2aXJ1cyAo
SElWKS1pbmZlY3RlZCBtZW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBJbmZlY3QgRGlzPC9z
ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgSm91cm5hbCBvZiBpbmZlY3Rpb3VzIGRpc2Vh
c2VzPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBJbmZlY3Qg
RGlzPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEpvdXJuYWwgb2YgaW5mZWN0aW91cyBkaXNlYXNl
czwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBJbmZl
Y3QgRGlzPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIEpvdXJuYWwgb2YgaW5mZWN0aW91cyBkaXNl
YXNlczwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjg0My04PC9wYWdlcz48dm9sdW1l
PjE2Mzwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxlZGl0aW9uPjE5OTEvMDQvMDE8L2VkaXRp
b24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlmdW5nYWwg
QWdlbnRzL2FkdmVyc2UgZWZmZWN0cy8qcGhhcm1hY29raW5ldGljcy90aGVyYXBldXRpYyB1c2U8
L2tleXdvcmQ+PGtleXdvcmQ+QXRvdmFxdW9uZTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQgU3R1
ZGllczwva2V5d29yZD48a2V5d29yZD5EcnVnIEV2YWx1YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+
RHJ1ZyBUb2xlcmFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SElWIEluZmVjdGlvbnMvKmNvbXBsaWNh
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+SGFsZi1MaWZlPC9rZXl3b3JkPjxrZXl3b3JkPkhvbW9z
ZXh1YWxpdHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8
L2tleXdvcmQ+PGtleXdvcmQ+TmFwaHRob3F1aW5vbmVzL2FkdmVyc2UgZWZmZWN0cy8qcGhhcm1h
Y29raW5ldGljcy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhLCBQ
bmV1bW9jeXN0aXMvZHJ1ZyB0aGVyYXB5LypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdv
cmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5MTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFw
cjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMjItMTg5OSAoUHJpbnQpJiN4RDsw
MDIyLTE4OTkgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIwMTA2Mzc8L2FjY2Vzc2lv
bi1udW0+PHdvcmstdHlwZT5DbGluaWNhbCBUcmlhbCYjeEQ7Q29udHJvbGxlZCBDbGluaWNhbCBU
cmlhbCYjeEQ7UmVzZWFyY2ggU3VwcG9ydCwgTm9uLVUuUy4gR292JmFwb3M7dCYjeEQ7UmVzZWFy
Y2ggU3VwcG9ydCwgVS5TLiBHb3YmYXBvczt0LCBQLkguUy48L3dvcmstdHlwZT48dXJscz48cmVs
YXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMDEwNjM3
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVj
b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRpeG9uPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
UmVjTnVtPjU5PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj41OTwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBwZjJ2bWQ1
ZGR4d2RwZjJ2eCI+NTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkRp
eG9uLCBSLjwvYXV0aG9yPjxhdXRob3I+UG96bmlhaywgQS4gTC48L2F1dGhvcj48YXV0aG9yPldh
dHQsIEguIE0uPC9hdXRob3I+PGF1dGhvcj5Sb2xhbiwgUC48L2F1dGhvcj48YXV0aG9yPlBvc25l
ciwgSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh
cnRtZW50IG9mIENsaW5pY2FsIFBoYXJtYWNvbG9neSwgV2VsbGNvbWUgUmVzZWFyY2ggTGFib3Jh
dG9yaWVzLCBLZW50LCBVbml0ZWQgS2luZ2RvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs
ZT5TaW5nbGUtZG9zZSBhbmQgc3RlYWR5LXN0YXRlIHBoYXJtYWNva2luZXRpY3Mgb2YgYSBub3Zl
bCBtaWNyb2ZsdWlkaXplZCBzdXNwZW5zaW9uIG9mIGF0b3ZhcXVvbmUgaW4gaHVtYW4gaW1tdW5v
ZGVmaWNpZW5jeSB2aXJ1cy1zZXJvcG9zaXRpdmUgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+QW50aW1pY3JvYiBBZ2VudHMgQ2hlbW90aGVyPC9zZWNvbmRhcnktdGl0bGU+PGFsdC10
aXRsZT5BbnRpbWljcm9iaWFsIGFnZW50cyBhbmQgY2hlbW90aGVyYXB5PC9hbHQtdGl0bGU+PC90
aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW50aW1pY3JvYiBBZ2VudHMgQ2hlbW90aGVy
PC9mdWxsLXRpdGxlPjxhYmJyLTE+QW50aW1pY3JvYmlhbCBhZ2VudHMgYW5kIGNoZW1vdGhlcmFw
eTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW50aW1p
Y3JvYiBBZ2VudHMgQ2hlbW90aGVyPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW50aW1pY3JvYmlhbCBh
Z2VudHMgYW5kIGNoZW1vdGhlcmFweTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjU1
Ni02MDwvcGFnZXM+PHZvbHVtZT40MDwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxlZGl0aW9u
PjE5OTYvMDMvMDE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFudGlmdW5nYWwgQWdlbnRzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZl
cnNlIGVmZmVjdHMvKnBoYXJtYWNva2luZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QXRvdmFxdW9u
ZTwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIEF2YWlsYWJpbGl0eTwva2V5d29yZD48a2V5
d29yZD5Gb29kLURydWcgSW50ZXJhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkhJViBTZXJvcG9z
aXRpdml0eS8qbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl
eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5OYXBodGhvcXVpbm9uZXMvYWRtaW5pc3RyYXRp
b24gJmFtcDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0cy8qcGhhcm1hY29raW5ldGljczwva2V5d29y
ZD48a2V5d29yZD5TdXNwZW5zaW9uczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4x
OTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+
PGlzYm4+MDA2Ni00ODA0IChQcmludCkmI3hEOzAwNjYtNDgwNCAoTGlua2luZyk8L2lzYm4+PGFj
Y2Vzc2lvbi1udW0+ODg1MTU3MDwvYWNjZXNzaW9uLW51bT48d29yay10eXBlPkNsaW5pY2FsIFRy
aWFsJiN4RDtDb250cm9sbGVkIENsaW5pY2FsIFRyaWFsPC93b3JrLXR5cGU+PHVybHM+PHJlbGF0
ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg1MTU3MDwv
dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj4xNjMxNTc8L2N1c3RvbTI+PGxhbmd1
YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 59, 63, 65 Elimination is primarily via the liver, with almost undetectable amounts (<0.6%) of drug being eliminated via the kidney. ADDIN EN.CITE <EndNote><Cite><Author>Rolan</Author><Year>1997</Year><RecNum>60</RecNum><DisplayText><style face="superscript">66</style></DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rolan, P. E.</author><author>Mercer, A. J.</author><author>Tate, E.</author><author>Benjamin, I.</author><author>Posner, J.</author></authors></contributors><auth-address>Department of Clinical Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.</auth-address><titles><title>Disposition of atovaquone in humans</title><secondary-title>Antimicrob Agents Chemother</secondary-title><alt-title>Antimicrobial agents and chemotherapy</alt-title></titles><periodical><full-title>Antimicrob Agents Chemother</full-title><abbr-1>Antimicrobial agents and chemotherapy</abbr-1></periodical><alt-periodical><full-title>Antimicrob Agents Chemother</full-title><abbr-1>Antimicrobial agents and chemotherapy</abbr-1></alt-periodical><pages>1319-21</pages><volume>41</volume><number>6</number><edition>1997/06/01</edition><keywords><keyword>Adult</keyword><keyword>Antiprotozoal Agents/*pharmacokinetics</keyword><keyword>Atovaquone</keyword><keyword>Bile/metabolism</keyword><keyword>Biliary Tract/metabolism</keyword><keyword>Biliary Tract Surgical Procedures</keyword><keyword>Carbon Radioisotopes/diagnostic use</keyword><keyword>Feces</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Naphthoquinones/*pharmacokinetics</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0066-4804 (Print)
0066-4804 (Linking)</isbn><accession-num>9174191</accession-num><urls><related-urls><url> Over 90% of drug excreted in bile was in the parent form. Elimination of atovaquone is complicated by the possibility of enterohepatic recirculation of drug, which may help explain atovaquone pharmacokinetic profiles where reduction and then increases in drug concentration are seen with time.In a study of atovaquone population pharmacokinetics, the oral clearance of atovaquone was increased in patients with higher body weight, with 60% increased clearance seen in an 80 kg patient compared to a 40 kg patient. ADDIN EN.CITE <EndNote><Cite><Author>Hussein</Author><Year>1997</Year><RecNum>2029</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>2029</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">2029</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hussein, Z.</author><author>Eaves, J.</author><author>Hutchinson, D. B.</author><author>Canfield, C. J.</author></authors></contributors><titles><title>Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum</title><secondary-title>Clin Pharmacol Ther</secondary-title></titles><pages>518-30</pages><volume>61</volume><number>5</number><keywords><keyword>Adolescence</keyword><keyword>Adult</keyword><keyword>Analysis of Variance</keyword><keyword>Antimalarials/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Computer Simulation</keyword><keyword>Databases, Factual</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Gabon</keyword><keyword>Human</keyword><keyword>Kenya</keyword><keyword>Malaria, Falciparum/blood/*drug therapy/metabolism</keyword><keyword>Male</keyword><keyword>Middle Age</keyword><keyword>Models, Biological</keyword><keyword>Naphthoquinones/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Philippines</keyword><keyword>Support, Non-U.S. Gov't</keyword><keyword>Thailand</keyword><keyword>Zambia</keyword></keywords><dates><year>1997</year></dates><label>97307201</label><urls></urls></record></Cite></EndNote>61 In the same study, the average oral clearance of atovaquone was higher in Oriental (8.49 L / h) and Malay (9.13 L / h) subjects compared to white (1-7.6 L / h) subjects. ADDIN EN.CITE <EndNote><Cite><Author>Hussein</Author><Year>1997</Year><RecNum>2029</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>2029</rec-number><foreign-keys><key app="EN" db-id="xsrz9pr0t5s92wefvzhxxttcvea2zxfp0vfr">2029</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hussein, Z.</author><author>Eaves, J.</author><author>Hutchinson, D. B.</author><author>Canfield, C. J.</author></authors></contributors><titles><title>Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum</title><secondary-title>Clin Pharmacol Ther</secondary-title></titles><pages>518-30</pages><volume>61</volume><number>5</number><keywords><keyword>Adolescence</keyword><keyword>Adult</keyword><keyword>Analysis of Variance</keyword><keyword>Antimalarials/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Computer Simulation</keyword><keyword>Databases, Factual</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Gabon</keyword><keyword>Human</keyword><keyword>Kenya</keyword><keyword>Malaria, Falciparum/blood/*drug therapy/metabolism</keyword><keyword>Male</keyword><keyword>Middle Age</keyword><keyword>Models, Biological</keyword><keyword>Naphthoquinones/blood/*pharmacokinetics/therapeutic use</keyword><keyword>Philippines</keyword><keyword>Support, Non-U.S. Gov't</keyword><keyword>Thailand</keyword><keyword>Zambia</keyword></keywords><dates><year>1997</year></dates><label>97307201</label><urls></urls></record></Cite></EndNote>61Drug interactionsAtovaquone is highly bound to plasma protein (>99.5%) and shows high affinity for human serum albumin.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ac2lsYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA 55 Furthermore, the half life of atovaquone is long, ranging around 50 to 84 hours and the major limiting factor to atovaquone clearance is likely its plasma protein binding.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2xhbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA 59, 63, 65 This suggests that any drug which reduces atovaquone plasma protein binding may potentially alter atovaquone tissue distribution and/or clearance. However, the authors can find no published articles investigating the drug-mediated displacement of atovaquone from plasma protein and the clinical impact of these interactions, and this area requires further research. The interaction observed between atovaquone and antiretrovirals, where efavirenz, lopinavir and ritonavir (all highly protein-bound drugs) reduced atovaquone plasma concentrations in HIV-infected patients, may involve atovaquone plasma-protein displacement, although this was not demonstrated.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTHVpbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTHVpbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA 67 This emphasises the importance of establishing the interactions between antimalarials, including atovaquone, and antiretrovirals.The potential for atovaquone to displace other protein-bound drugs has been investigated. A case study has recently been published which describes a potential interaction between the anticoagulant drug warfarin and atovaquone, where the author suggests that atovaquone caused an increase in free warfarin concentrations to super-therapeutic levels.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaWRhbGdvPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaWRhbGdvPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
UmVjTnVtPjYyPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
Njg8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42MjwvcmVjLW51bWJl
cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBw
ZjJ2bWQ1ZGR4d2RwZjJ2eCI+NjI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i
Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0
aG9yPkhpZGFsZ28sIEsuPC9hdXRob3I+PGF1dGhvcj5MeWxlcywgQS48L2F1dGhvcj48YXV0aG9y
PkRlYW4sIFMuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl
c3M+Q1ZTIENhcmVtYXJrLCBKYWNrc29udmlsbGUsIEZMLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRp
dGxlcz48dGl0bGU+QSBwb3RlbnRpYWwgaW50ZXJhY3Rpb24gYmV0d2VlbiB3YXJmYXJpbiBhbmQg
YXRvdmFxdW9uZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gUGhhcm1hY290aGVyPC9zZWNv
bmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaGUgQW5uYWxzIG9mIHBoYXJtYWNvdGhlcmFweTwvYWx0
LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFubiBQaGFybWFjb3RoZXI8
L2Z1bGwtdGl0bGU+PGFiYnItMT5UaGUgQW5uYWxzIG9mIHBoYXJtYWNvdGhlcmFweTwvYWJici0x
PjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIFBoYXJtYWNvdGhl
cjwvZnVsbC10aXRsZT48YWJici0xPlRoZSBBbm5hbHMgb2YgcGhhcm1hY290aGVyYXB5PC9hYmJy
LTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+ZTM8L3BhZ2VzPjx2b2x1bWU+NDU8L3ZvbHVtZT48
bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDEwLzEyLzMwPC9lZGl0aW9uPjxrZXl3b3Jkcz48
a2V5d29yZD5BSURTLVJlbGF0ZWQgT3Bwb3J0dW5pc3RpYyBJbmZlY3Rpb25zL2NvbXBsaWNhdGlv
bnMvZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkFudGljb2FndWxhbnRzL2FkbWluaXN0
cmF0aW9uICZhbXA7IGRvc2FnZS8qYWR2ZXJzZSBlZmZlY3RzL3RoZXJhcGV1dGljIHVzZTwva2V5
d29yZD48a2V5d29yZD5BbnRpZnVuZ2FsIEFnZW50cy8qYWR2ZXJzZSBlZmZlY3RzL3RoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BdG92YXF1b25lLyphZHZlcnNlIGVmZmVjdHMvdGhl
cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgSW50ZXJhY3Rpb25zPC9rZXl3b3Jk
PjxrZXl3b3JkPkRydWcgTW9uaXRvcmluZzwva2V5d29yZD48a2V5d29yZD5IZW1vcnJoYWdlLypl
dGlvbG9neS9wcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkludGVybmF0aW9uYWwgTm9ybWFsaXplZCBSYXRpbzwva2V5d29y
ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPlBuZXVtb2N5c3RpcyBqaXJvdmVjaWk8L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlh
LCBQbmV1bW9jeXN0aXMvYmxvb2QvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHkvbWljcm9iaW9s
b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFyeSBFbWJvbGlzbS9jb21wbGljYXRpb25zL2Ry
dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdv
cmQ+VmVub3VzIFRocm9tYm9zaXMvY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHk8L2tleXdvcmQ+
PGtleXdvcmQ+Vml0YW1pbiBLL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hbnRhZ29uaXN0
cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPldhcmZhcmluL2FkbWluaXN0cmF0
aW9uICZhbXA7IGRvc2FnZS8qYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy90aGVyYXBldXRp
YyB1c2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRh
dGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NDItNjI3MCAo
RWxlY3Ryb25pYykmI3hEOzEwNjAtMDI4MCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+
MjExODkzNjM8L2FjY2Vzc2lvbi1udW0+PHdvcmstdHlwZT5DYXNlIFJlcG9ydHM8L3dvcmstdHlw
ZT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1
Ym1lZC8yMTE4OTM2MzwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv
dXJjZS1udW0+MTAuMTM0NS9hcGguMVA0OTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxsYW5n
dWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 68 A separate investigation found that atovaquone did not alter the pharmacokinetics of the antiepileptic drug phenytoin, another highly protein-bound drug which is susceptible to displacement interactions.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXZpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXZpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl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ADDIN EN.CITE.DATA 69 The evidence that atovaquone can compete with other drugs for plasma protein binding is lacking, although further investigations are required to fully understand this potential factor in atovaquone pharmacokinetics.Atovaquone exposure is markedly decreased when taken concomitantly with the antibiotic drug rifampicin and therefore co-administration of atovaquone and rifampicin is not recommended. ADDIN EN.CITE <EndNote><Cite><Author>Sousa</Author><Year>2008</Year><RecNum>64</RecNum><DisplayText><style face="superscript">70</style></DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sousa, M.</author><author>Pozniak, A.</author><author>Boffito, M.</author></authors></contributors><auth-address>St Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.</auth-address><titles><title>Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs</title><secondary-title>J Antimicrob Chemother</secondary-title><alt-title>The Journal of antimicrobial chemotherapy</alt-title></titles><periodical><full-title>J Antimicrob Chemother</full-title></periodical><pages>872-8</pages><volume>62</volume><number>5</number><edition>2008/08/21</edition><keywords><keyword>Antimalarials/*pharmacokinetics/pharmacology</keyword><keyword>Drug Interactions</keyword><keyword>Humans</keyword><keyword>Rifabutin/*pharmacokinetics/pharmacology</keyword><keyword>Rifampin/*pharmacokinetics/pharmacology</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1460-2091 (Electronic)
0305-7453 (Linking)</isbn><accession-num>18713760</accession-num><work-type>Review</work-type><urls><related-urls><url> The mechanism behind this interaction is not fully understood, although the ability of rifampicin to induce activity of metabolism enzymes and drug transporters is assumed to be responsible. However, no metabolite of atovaquone has been identified in humans, and the impact of individual enzymes and transporters on atovaquone disposition is unclear.There is evidence that atovaquone can inhibit cytochrome P450 enzymes, although data has been generated in vitro and the relevance to clinical drug interactions is unknown. Atovaquone inhibited the metabolism of 50 ?M 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC) by recombinant CYP3A4, with an IC50 of 4.7 ?M.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 52 Similarly, sulfamethoxazole (SMX) metabolism by recombinant CYP2C9 was inhibited by atovaquone, with a Ki of 15 ?M.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsZXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsZXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 71 However, when atovaquone was pre-incubated with human serum and centrifuge-filtered to remove protein before use, no CYP2C9 inhibitory activity was observed. This suggests that, although atovaquone has the capacity to inhibit CYP3A4 and CYP2C9 in vitro, the high plasma protein binding (>99%) of atovaquone may prevent significant enzyme inhibition in patients. However, aA recent case study described a HIV-infected female with a marked increase in plasma concentrations of antiretroviral drugs etravirine (+55%) and unboosted saquinavir (+274%) following atovaquone / proguanil prophylaxis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub21tYXNpPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub21tYXNpPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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ADDIN EN.CITE.DATA 72 In the same study, raltegravir plasma concentrations were unchanged following atovaquone/proguanil prophylaxis. The evidence that atovaquone/proguanil prophylaxis increases exposure of etravirine and saquinavir (both cytochrome P450 substrates) but not raltegravir (no affinity for cytochrome P450 enzymes) suggests atovaquone, proguanil, or indeed both drugs, may be inhibiting cytochrome P450 activity.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hvbGxlci1HeXVyZTwvQXV0aG9yPjxZZWFyPjIwMDk8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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hvbGxlci1HeXVyZTwvQXV0aG9yPjxZZWFyPjIwMDk8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=
ADDIN EN.CITE.DATA 73-75Co-administration of atovaquone and the nucleoside reverse transcriptase inhibitor zidovudine increased the exposure (33% increase in AUC0-8h, p < 0.05) and decreased the oral clearance (25% reduction, p < 0.05) of zidovudine in HIV-infected patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 76 Furthermore, patients taking atovaquone showed a trend towards lower zidovudine-glucuronide plasma concentrations (6% reduction in AUC0-8h, p < 0.1) and a significant decrease in the ratio between zidovudine-glucuronide and plasma concentrations (30% reduction, p < 0.05). Atovaquone exposure was unchanged when co-administered with zidovudine. The atovaquone-mediated 33% increase in zidovudine exposure is in itself unlikely to cause increased hematologic toxicity, although caution is advised in patients taking additional drugs with similar toxicity profiles to zidovudine.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 76 Also, increased zidovudine plasma concentrations and reduced zidovudine glucuronidation may potentially lead to increased formation of the cytochrome P450-mediated zidovudine metabolite, 3’-amino-3’-deoxythymidine, which shows seven-fold higher toxicity in bone marrow cells compared to the parent drug.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmV0dG9uPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmV0dG9uPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48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ADDIN EN.CITE.DATA 77The increased exposure and decreased clearance of zidovudine suggests that atovaquone is inhibiting the glucuronidation of zidovudine. The primary enzyme involved in zidovudine glucuronidation is uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B7.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWxhbmdlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWxhbmdlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE.DATA 78 Therefore, clearance of UGT2B7 substrates, such as the anti-HIV drug efavirenz, may also be influenced by atovaquone and further investigations are warranted in this area.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWxhbmdlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWxhbmdlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE.DATA 78Atovaquone did not alter the exposure of the anti-HIV protease inhibitor drug indinavir in healthy volunteers. ADDIN EN.CITE <EndNote><Cite><Author>Emmanuel</Author><Year>1998</Year><RecNum>73</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="2sraw9wxs55r55er550pf2vmd5ddxwdpf2vx">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Emmanuel, A.</author><author>Gillotin, C.</author><author>Farinotti, R.</author></authors></contributors><titles><title>Atovaquone suspension and indinavir have minimal pharmacokinetic interactions</title><secondary-title>12th International Conference on AIDS, Geneva, Swizterland, abstract 12384</secondary-title></titles><periodical><full-title>12th International Conference on AIDS, Geneva, Swizterland, abstract 12384</full-title></periodical><dates><year>1998</year></dates><accession-num>8864327</accession-num><urls></urls><custom2>2042667</custom2></record></Cite></EndNote>79 Indinavir is a substrate of the drug efflux transporter, ABCB1, and the absence of any effect of atovaquone on indinavir pharmacokinetics suggests that atovaquone is not altering the activity of ABCB1, although this has not been confirmed.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2NobWFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2NobWFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
UmVjTnVtPjc0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
ODA8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj43NDwvcmVjLW51bWJl
cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjJzcmF3OXd4czU1cjU1ZXI1NTBw
ZjJ2bWQ1ZGR4d2RwZjJ2eCI+NzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i
Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0
aG9yPkhvY2htYW4sIEouIEguPC9hdXRob3I+PGF1dGhvcj5DaGliYSwgTS48L2F1dGhvcj48YXV0
aG9yPk5pc2hpbWUsIEouPC9hdXRob3I+PGF1dGhvcj5ZYW1hemFraSwgTS48L2F1dGhvcj48YXV0
aG9yPkxpbiwgSi4gSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk
cmVzcz5EZXBhcnRtZW50IG9mIERydWcgTWV0YWJvbGlzbSwgTWVyY2sgUmVzZWFyY2ggTGFib3Jh
dG9yaWVzLCBXZXN0IFBvaW50LCBQQSAxOTQ4NiwgVVNBLiBqZXJvbWVfaG9jaG1hbkBtZXJjay5j
b208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbmZsdWVuY2Ugb2YgUC1nbHljb3Byb3Rl
aW4gb24gdGhlIHRyYW5zcG9ydCBhbmQgbWV0YWJvbGlzbSBvZiBpbmRpbmF2aXIgaW4gQ2Fjby0y
IGNlbGxzIGV4cHJlc3NpbmcgY3l0b2Nocm9tZSBQLTQ1MCAzQTQ8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+SiBQaGFybWFjb2wgRXhwIFRoZXI8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRo
ZSBKb3VybmFsIG9mIHBoYXJtYWNvbG9neSBhbmQgZXhwZXJpbWVudGFsIHRoZXJhcGV1dGljczwv
YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkpvdXJuYWwgb2YgUGhh
cm1hY29sb2d5IGFuZCBFeHBlcmltZW50YWwgVGhlcmFwZXV0aWNzPC9mdWxsLXRpdGxlPjxhYmJy
LTE+SiBQaGFybWFjb2wgRXhwIFRoZXI8L2FiYnItMT48L3BlcmlvZGljYWw+PHBhZ2VzPjMxMC04
PC9wYWdlcz48dm9sdW1lPjI5Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjE5
OTkvMTIvMjI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkJpb2xvZ2ljYWwgVHJhbnNwb3J0
LCBBY3RpdmU8L2tleXdvcmQ+PGtleXdvcmQ+Q2Fjby0yIENlbGxzPC9rZXl3b3JkPjxrZXl3b3Jk
PkNob2xlY2FsY2lmZXJvbDwva2V5d29yZD48a2V5d29yZD5DeWNsb3Nwb3JpbmUvKnBoYXJtYWNv
bG9neTwva2V5d29yZD48a2V5d29yZD5DeXRvY2hyb21lIFAtNDUwIENZUDNBPC9rZXl3b3JkPjxr
ZXl3b3JkPkN5dG9jaHJvbWUgUC00NTAgRW56eW1lIFN5c3RlbS9nZW5ldGljcy8qbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5EcnVnIEludGVyYWN0aW9uczwva2V5d29yZD48a2V5d29yZD5I
SVYgUHJvdGVhc2UgSW5oaWJpdG9ycy8qcGhhcm1hY29raW5ldGljczwva2V5d29yZD48a2V5d29y
ZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5kaW5hdmlyLypwaGFybWFjb2tpbmV0aWNzPC9r
ZXl3b3JkPjxrZXl3b3JkPkludGVzdGluYWwgQWJzb3JwdGlvbi8qZHJ1ZyBlZmZlY3RzPC9rZXl3
b3JkPjxrZXl3b3JkPk1peGVkIEZ1bmN0aW9uIE94eWdlbmFzZXMvZ2VuZXRpY3MvKm1ldGFib2xp
c208L2tleXdvcmQ+PGtleXdvcmQ+UC1HbHljb3Byb3RlaW4vKnBoeXNpb2xvZ3k8L2tleXdvcmQ+
PGtleXdvcmQ+VGltZSBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlR1bW9yIENlbGxzLCBDdWx0
dXJlZDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAwPC95ZWFyPjxwdWItZGF0
ZXM+PGRhdGU+SmFuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAyMi0zNTY1IChQ
cmludCkmI3hEOzAwMjItMzU2NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTA2MDQ5
NjQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNi
aS5ubG0ubmloLmdvdi9wdWJtZWQvMTA2MDQ5NjQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA 80Safety and Toxicology Atovaquone has been found to be generally well tolerated and causes few side effects. Adverse events are generally mild and include rash, fever, vomiting, diarrhoea, abdominal pain and headache. Indeed, overdoses as large as 31,500 mg have been reported causing little or no symptomatology.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGV1bmc8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGV1bmc8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 81 A significant concern for the development of novel antimalarials targeting the parasite bc1, is host mitochondrial toxicity. In animal models this manifests itself as acute toxicity (presumed to be cardiotoxicity). Current development projects use in vitro counter-screens such as human bc1 screening or human cell lines grown on galactose, making these cells more reliant on mitochondrial metabolism by circumventing the Crabtree effect PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJyb3F1aW48L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJyb3F1aW48L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy
PjxSZWNOdW0+MTg3NDU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2Ny
aXB0Ij44Mjwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE4NzQ1PC9y
ZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0ieHNyejlwcjB0NXM5
MndlZnZ6aHh4dHRjdmVhMnp4ZnAwdmZyIj4xODc0NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt
dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh
dXRob3JzPjxhdXRob3I+TWFycm9xdWluLCBMLiBELjwvYXV0aG9yPjxhdXRob3I+SHluZXMsIEou
PC9hdXRob3I+PGF1dGhvcj5EeWtlbnMsIEouIEEuPC9hdXRob3I+PGF1dGhvcj5KYW1pZXNvbiwg
Si4gRC48L2F1dGhvcj48YXV0aG9yPldpbGwsIFkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp
YnV0b3JzPjxhdXRoLWFkZHJlc3M+UGZpemVyIERTUkQsIFNhbiBEaWVnbywgQ0EgOTIxMjEsIFVT
QS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5DaXJjdW12ZW50aW5nIHRoZSBDcmFidHJl
ZSBlZmZlY3Q6IHJlcGxhY2luZyBtZWRpYSBnbHVjb3NlIHdpdGggZ2FsYWN0b3NlIGluY3JlYXNl
cyBzdXNjZXB0aWJpbGl0eSBvZiBIZXBHMiBjZWxscyB0byBtaXRvY2hvbmRyaWFsIHRveGljYW50
czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Ub3hpY29sIFNjaTwvc2Vjb25kYXJ5LXRpdGxlPjxh
bHQtdGl0bGU+VG94aWNvbG9naWNhbCBzY2llbmNlcyA6IGFuIG9mZmljaWFsIGpvdXJuYWwgb2Yg
dGhlIFNvY2lldHkgb2YgVG94aWNvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs
PjxmdWxsLXRpdGxlPlRveGljb2wgU2NpPC9mdWxsLXRpdGxlPjxhYmJyLTE+VG94aWNvbG9naWNh
bCBzY2llbmNlcyA6IGFuIG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIFNvY2lldHkgb2YgVG94aWNv
bG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+VG94
aWNvbCBTY2k8L2Z1bGwtdGl0bGU+PGFiYnItMT5Ub3hpY29sb2dpY2FsIHNjaWVuY2VzIDogYW4g
b2ZmaWNpYWwgam91cm5hbCBvZiB0aGUgU29jaWV0eSBvZiBUb3hpY29sb2d5PC9hYmJyLTE+PC9h
bHQtcGVyaW9kaWNhbD48cGFnZXM+NTM5LTQ3PC9wYWdlcz48dm9sdW1lPjk3PC92b2x1bWU+PG51
bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAwNy8wMy8xNjwvZWRpdGlvbj48a2V5d29yZHM+PGtl
eXdvcmQ+QWRlbm9zaW5lIFRyaXBob3NwaGF0ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk
PkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBMaW5lPC9rZXl3b3JkPjxrZXl3b3Jk
PkN1bHR1cmUgTWVkaWEvKmNoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5Eb3NlLVJlc3BvbnNl
IFJlbGF0aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9ycy90
b3hpY2l0eTwva2V5d29yZD48a2V5d29yZD5HYWxhY3Rvc2UvKm1ldGFib2xpc20vKnBoYXJtYWNv
bG9neTwva2V5d29yZD48a2V5d29yZD5HbHVjb3NlLyptZXRhYm9saXNtLypwaGFybWFjb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+R2x5Y29seXNpcy8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3
b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NaXRvY2hvbmRyaWEsIExpdmVyLypkcnVnIGVm
ZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFBob3NwaG9yeWxhdGlvbi8qZHJ1ZyBl
ZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPk94eWdlbiBDb25zdW1wdGlvbi9kcnVnIGVmZmVjdHM8
L2tleXdvcmQ+PGtleXdvcmQ+VG94aWNpdHkgVGVzdHMvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdv
cmQ+VW5jb3VwbGluZyBBZ2VudHMvdG94aWNpdHk8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+
PHllYXI+MjAwNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48
L2RhdGVzPjxpc2JuPjEwOTYtNjA4MCAoUHJpbnQpJiN4RDsxMDk2LTA5MjkgKExpbmtpbmcpPC9p
c2JuPjxhY2Nlc3Npb24tbnVtPjE3MzYxMDE2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzE3MzYxMDE2PC91
cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDkz
L3RveHNjaS9rZm0wNTI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxsYW5ndWFnZT5lbmc8L2xh
bmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 82. However these projects are hampered by the absence of industry standards relating to pre-clinical or clinical mitochondrial toxicity.Conclusion Despite the extensive use of Atovaquone-Proguanil, there remains a considerable knowledge gap concerning its pharmacology. The rollout of generics following the expiry of the patent will undoubtedly see an increase in Atovaquone-Proguanil usage that will be closely followed by an increase in the treatment failures. Clearly, if the community is to manage this issue and develop improved derivatives, more effort needs to be placed into understanding the PK-PD mechanisms underpinning Atovaquone-Proguanil treatment failure.AcknowledgementsThe authors acknowledge grant support from the Leverhulme Trust, Wellcome Trust, EU FP7, Medical Research Council (MRC) and Medicines for Malaria Venture (MMV).Transparency DeclarationNone to declare.References ADDIN EN.REFLIST 1.Hudson AT. Atovaquone - a Novel Broad-Spectrum Antiinfective Drug. Parasitol Today 1993; 9: 66-8.2.McKeage K, Scott LJ. Atovaquone/Proguanil - A review of its use for the prophylaxis of Plasmodium falciparum malaria. Drugs 2003; 63: 597-623.3.Nakato H, Vivancos R, Hunter PR. A systematic review and meta-analysis of the effectiveness and safety of atovaquone-proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemoth 2007; 60: 929-36.4.Looareesuwan S, Chulay JD, Canfield CJ et al. Malarone (R) (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria. Am J Trop Med Hyg 1999; 60: 533-41.5.Spencer CM, Goa KL. Atovaquone - a Review of Its Pharmacological Properties and Therapeutic Efficacy in Opportunistic Infections. Drugs 1995; 50: 176-96.6.Haile LG, Flaherty JF. Atovaquone - a Review. Annals of Pharmacotherapy 1993; 27: 1488-94.7.Osei-Akoto A, Orton LC, Owusu-Ofori S. Atovaquone-proguanil for treating uncomplicated malaria. Cochrane DB Syst Rev 2005; CD004529: 1-53. 8.Lalloo DG, Hill DR. Preventing malaria in travellers. BMJ 2008; 336: 1362-6.9.LaRocque RC, Rao SR, Lee J et al. Global TravEpiNet: a national consortium of clinics providing care to international travelers--analysis of demographic characteristics, travel destinations, and pretravel healthcare of high-risk US international travelers, 2009-2011. Clin Infect Dis 2012; 54: 455-62.10.Fieser LF, Richardson AP. Naphthoquinone Antimalarials .2. Correlation of Structure and Activity against P-Lophurae in Ducks. J Am Chem Soc 1948; 70: 3156-65.11.Fieser LF, Heymann H, Seligman AM. Naphthoquinone Antimalarials .20. Metabolic Degradation. J Pharmacol Exp Ther 1948; 94: 112-24.12.Fieser LF, Chang FC, Dauben WG et al. Naphthoquinone Antimalarials .18. Metabolic Oxidation Products. J Pharmacol Exp Ther 1948; 94: 85-96.13.Fieser LF, Schirmer JP, Archer S et al. Naphthoquinone Antimalarials .29. 2-Hydroxy-3-(Omega-Cyclohexylalkyl)-1,4-Naphthoquinones. J Med Chem 1967; 10: 513-7.14.Fawaz G, Haddad FS. The Effect of Lapinone (M-2350) on P-Vivax Infection in Man. Am J Trop Med 1951; 31: 569-71.15.Hudson AT, Randall AW, Fry M et al. Novel Anti-Malarial Hydroxynaphthoquinones with Potent Broad-Spectrum Anti-Protozoal Activity. Parasitology 1985; 90: 45-55.16.Hudson AT, Pether MJ, Randall AW et al. Invitro Activity of 2-Cycloalkyl-3-Hydroxy-1,4-Naphthoquinones against Theileria, Eimeria and Plasmodia Species. Eur J Med Chem 1986; 21: 271-5.17.Hudson AT, Dickins M, Ginger CD et al. 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp Clin Res 1991; 17: 427-35.18.Patent WO9320044 , 1,4 NAPHTHOQUINONE DERIVTIVES WITH ANTI-PROTOZOAL AND ANTI-PARASITIC ACTIVITY. US 4981874, Medicaments. DR, Clark MP. Synthesis of atovaquone. Tetrahedron Lett 1998; 39: 7629-32.21.Patent WO/2010/001379 A Process for preparing Atovaquone and associate intermediates. WO/2010/001378 Process for the epimerization of atovaquone isomer, Atovaquone intermediates and mixtures thereof . WO/2008/122988, 2008. Process for preparation of Atovaquone and the conversion of cis-isomer to trans-isomer. AL, Hill DR. Antiparasitic agent atovaquone. Antimicrob Agents Chemother 2002; 46: 1163-73.25.Biagini GA, Fisher N, Shone AE et al. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc Natl Acad Sci U S A 2012; 109: 8298-303.26.Zhang Y, Clark JA, Connelly MC et al. Lead Optimization of 3-Carboxyl-4(1H)-Quinolones to Deliver Orally Bioavailable Antimalarials. J Med Chem 2012; 55: 4205-19.27.Cross RM, Namelikonda NK, Mutka TS et al. Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones. J Med Chem 2011; 54: 8321-7.28.Barton V, Fisher N, Biagini GA et al. Inhibiting Plasmodium cytochrome bc1: a complex issue. Curr Opin Chem Biol 2010; 14: 440-6.29.Winter RW, Kelly JX, Smilkstein MJ et al. Optimization of endochin-like quinolones for antimalarial activity. Exp Parasitol 2011; 127:545-51.30.Winter RW, Kelly JX, Smilkstein MJ et al. Antimalarial quinolones: Synthesis, potency, and mechanistic studies. Exp Parasitol 2008; 118: 487–97.31.Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4- (4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol 1992; 43: 1545-53.32.Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem 1997; 272: 3961-6.33.Biagini GA, Viriyavejakul P, O'Neill P M et al. Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrob Agents Chemother 2006; 50: 1841-51.34.Seymour KK, Yeo AE, Rieckmann KH et al. dCTP levels are maintained in Plasmodium falciparum subjected to pyrimidine deficiency or excess. Ann Trop Med Parasitol 1997; 91: 603-9.35.Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol 1985; 14: 97-109.36.Painter HJ, Morrisey JM, Mather MW et al. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 2007; 446: 88-91.37.Bulusu V, Jayaraman V, Balaram H. Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum. J Biol Chem 2011; 286: 9236-45.38.White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41: 1413-22.39.Dembele L, Gego A, Zeeman AM et al. Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS One 2011; 6: e18162.40.Kessl JJ, Meshnick SR, Trumpower BL. Modeling the molecular basis of atovaquone resistance in parasites and pathogenic fungi. Trends Parasitol 2007; 23: 494-501.41.Korsinczky M, Chen N, Kotecka B et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000; 44: 2100-8.42.Musset L, Bouchaud O, Matheron S et al. Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations. Microbes Infect 2006; 8: 2599-604.43.Berry A, Senescau A, Lelievre J et al. Prevalence of Plasmodium falciparum cytochrome b gene mutations in isolates imported from Africa, and implications for atovaquone resistance. Trans R Soc Trop Med Hyg 2006; 100: 986-8.44.Fivelman QL, Butcher GA, Adagu IS et al. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar J 2002; 1: 1.45.Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis 2003; 37: 450-1.46.Fisher N, Majid RA, Antoine T et al. Cytochrome b Mutation Y268S Conferring Atovaquone Resistance Phenotype in Malaria Parasite Results in Reduced Parasite bc(1) Catalytic Turnover and Protein Expression. J Biol Chem 2012; 287: 9731-41.47.Chiodini PL, Conlon CP, Hutchinson DB et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother 1995; 36: 1073-8.48.Looareesuwan S, Viravan C, Webster HK et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996; 54: 62-6.49.Pesole G, Gissi C, De Chirico A et al. Nucleotide substitution rate of mammalian mitochondrial genomes. J Mol Evol 1999; 48: 427-34.50.Smilkstein MJ, Forquer I, Kanazawa A et al. A drug-selected Plasmodium falciparum lacking the need for conventional electron transport. Mol Biochem Parasitol 2008; 159: 64-8.51.Ding XC, Ubben D, Wells TN. A framework for assessing the risk of resistance for anti-malarials in development. Malar J 2012; 11: 292.52.Thapar MM, Ashton M, Lindegardh N et al. Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol 2002; 58: 19-27.53.Khositnithikul R, Tan-Ariya P, Mungthin M. In vitro atovaquone/proguanil susceptibility and characterization of the cytochrome b gene of Plasmodium falciparum from different endemic regions of Thailand. Malar J 2008; 7: 23.54.Biagini GA, Fisher N, Berry N et al. Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Mol Pharmacol 2008; 73: 1347-55.55.Zsila F, Fitos I. Combination of chiroptical, absorption and fluorescence spectroscopic methods reveals multiple, hydrophobicity-driven human serum albumin binding of the antimalarial atovaquone and related hydroxynaphthoquinone compounds. Org Biomol Chem 2010; 8: 4905-14.56.Hughes W, Leoung G, Kramer F et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. The New England journal of medicine 1993; 328: 1521-7.57.Wichmann O, Muehlen M, Gruss H et al. Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. Malar J 2004; 3: 14.58.Durand R, Prendki V, Cailhol J et al. Plasmodium falciparum malaria and atovaquone-proguanil treatment failure. Emerg Infect Dis 2008; 14: 320-2.59.Hughes WT, Kennedy W, Shenep JL et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis 1991; 163: 843-8.60.Rosenberg DM, McCarthy W, Slavinsky J et al. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. Aids 2001; 15: 211-4.61.Hussein Z, Eaves J, Hutchinson DB et al. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharmacol Ther 1997; 61: 518-30.62.Nicolaides E, Galia E, Efthymiopoulos C et al. Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res 1999; 16: 1876-82.63.Rolan PE, Mercer AJ, Weatherley BC et al. Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Brit J Clin Pharmacol 1994; 37: 13-20.64.Chotivanich K, Mungthin M, Ruengweerayuth R et al. The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against plasmodium falciparum. Malar J 2012; 11: 177.65.Dixon R, Pozniak AL, Watt HM et al. Single-dose and steady-state pharmacokinetics of a novel microfluidized suspension of atovaquone in human immunodeficiency virus-seropositive patients. Antimicrob Agents Chemother 1996; 40: 556-60.66.Rolan PE, Mercer AJ, Tate E et al. Disposition of atovaquone in humans. Antimicrob Agents Chemother 1997; 41: 1319-21.67.van Luin M, Van der Ende ME, Richter C et al. Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. Aids 2010; 24: 1223-6.68.Hidalgo K, Lyles A, Dean SR. A potential interaction between warfarin and atovaquone. Ann Pharmacother 2011; 45: e3.69.Davis JD, Dixon R, Khan AZ et al. Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers. Brit J Clin Pharmacol 1996; 42: 246-8.70.Sousa M, Pozniak A, Boffito M. Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. J Antimicrob Chemother 2008; 62: 872-8.71.Miller JL, Trepanier LA. Inhibition by atovaquone of CYP2C9-mediated sulphamethoxazole hydroxylamine formation. Eur J Clin Pharmacol 2002; 58: 69-72.72.Tommasi C, Bellagamba R, Tempestilli M et al. Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis. Malar J 2011; 10: 141.73.Scholler-Gyure M, Kakuda TN, Raoof A et al. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokine 2009; 48: 561-74.74.Eagling VA, Wiltshire H, Whitcombe IW et al. CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica; the fate of foreign compounds in biological systems 2002; 32: 1-17.75.Kassahun K, McIntosh I, Cui D et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dis 2007; 35: 1657-63.76.Lee BL, Tauber MG, Sadler B et al. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996; 59: 14-21.77.Cretton EM, Xie MY, Bevan RJ et al. Catabolism of 3'-azido-3'-deoxythymidine in hepatocytes and liver microsomes, with evidence of formation of 3'-amino-3'-deoxythymidine, a highly toxic catabolite for human bone marrow cells. Mol Pharmacol 1991; 39: 258-66.78.Belanger AS, Caron P, Harvey M et al. Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dis 2009; 37: 1793-6.79.Emmanuel A, Gillotin C, Farinotti R. Atovaquone suspension and indinavir have minimal pharmacokinetic interactions. In: Abstract of the 12th International Conference on AIDS, Geneva, Swizterland, 1998. Abstract 12384.80.Hochman JH, Chiba M, Nishime J et al. Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther 2000; 292: 310-8.81.Cheung TW. Overdose of atovaquone in a patient with AIDS. AIDS 1999; 13: 1984-5.82.Marroquin LD, Hynes J, Dykens JA et al. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicological sciences : an official journal of the Society of Toxicology 2007; 97: 539-47.83.Solmaz SR, Hunte C. Structure of complex III with bound cytochrome c in reduced state and definition of a minimal core interface for electron transfer. J Biol Chem 2008; 283: 17542-9.Figure 1. Historical development of atovaquone and its PK properties (m-measured, p-predicted).Figure 2: Synthetic routes used to synthesise atovaquoneFigure 3: Panel (a). Cartoon representation of the yeast cytochrome bc1 complex (3CX5.PDB, with atovaquone modelled at the Qo site (boxed area).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2xtYXo8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2xtYXo8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 83 The bc1 complex is a structural and functional homodimer with a molecular mass of approximately 480 kDa, consisting of 10 discrete subunits per monomer in yeast and P. falciparum. The electron-transferring catalytic unit of one monomer is highlighted; cytochrome b is represented in orange, cytochrome c1 in blue and the Rieske iron-sulpur protein (ISP) in green. Haem groups (cyt b and cyt c1) are shown in red. The remaining subunits of the complex are rendered in grey. Panel (b) Molecular model of atovaquone (ATO) bound to the Qo site of the bc1 complex. Subunits are coloured as in panel (a). Atovaquone was modelled into the Qo site of cytochrome b as described by Fisher N et al.46 Hydrogen-bonding interactions between the naphthoquinone headgroup of atovaquone and sidechains of Glu-272 (cyt b) and His-181 (ISP) are indicated by yellow lines. The positions of haem bl (cyt b) and the ISP [2Fe2S] cluster are also shown.Figure 4. Atovaquone plasma concentration-time profile after single dose of Malarone in 13 healthy individuals. Used with permission from the study by Thaper et al.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGFwYXI8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 52 ADDIN ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- the university of scranton address
- the university of hong kong
- wharton school of the university of pennsylvania
- the university of scranton tuition
- the university of scranton
- the university of hk
- the university of scranton jobs
- the university of north texas
- welcome to the team letter
- the university of philosophical research
- the university of scranton players
- the university of scranton calendar