A Study on the effect of LOSARTAN on the pharmacokinetics ...



Study on Effect of Omeprazole on the Pharmacokinetics and Antidepressant Activity of Sertraline

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

BY

MAMATHA B C B.Pharm.

UNDER THE GUIDANCE OF

Mrs.NC NAGALAKSHMI M. Pharm.

Assistant Professor

MALLIGE COLLEGE OF PHARMACY, BANGALORE.

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MALLIGE COLLEGE OF PHARMACY

#71 SILVEPURA, BANGALORE 90

Rajiv Gandhi University of Health Sciences,

Karnataka, Bangalore.

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

|01 |Name and Address of the Candidate |Mamatha BC. |

| | |D/O chidananda swamy |

| | |Ballekere, Tiptur /T/, Tumkur /D/ |

|02 |Name of the Institution |Mallige College Of Pharmacy |

| | |#71 Silvepura, |

| | |Post : Chikkabanavara |

| | |Bangalore 90 |

|03 |Course of the Study Branch |M.Pharm (Pharmacology) |

|04 |Date of Admission to course |12.12.2011 |

|05 |Title of the Topic |Study on Effect of Omeprazole on the Pharmacokinetics and |

| | |Antidepressant Activity of Sertraline. |

|06 |Brief resume of the intended work |Enclosure – I |

| |6.1. Need for the Study | |

| |6.2. Review of the Literature |Enclosure – II |

| |6.3. Objective of the Study |Enclosure – III |

|07 |Materials and Methods | |

| |7.1. Source of data |Enclosure – IV |

| |7.2. Methods of collection of data |Enclosure – V |

| |7.3. Does the study require any Investigations on |Enclosure – VI |

| |animals? | |

| |If yes give details | |

| |7.4. Has ethical clearance been obtained from your | Yes |

| |institution in case of 7.3 | |

|08 |List of References |Enclosure – VII |

|09 |Signature of the Candidate |(MAMATHA) |

|10 |Remarks of the Guide |The present research work is original and not published in any of |

| | |the journals with best of my knowledge upon extensive literature |

| | |review. This work will be carried out in the Pharmacology laboratory|

| | |by Miss. Mamatha BC under my supervision. |

|11 |Name and Designation of | |

| |(in Block Letters) | |

| |11.1. Guide |Mrs.NC NAGALAKSHMIM. Pharm. |

| | |Assistant Professor |

| | |Mallige College Of Pharmacy, |

| | |Bangalore, Karnataka. |

| | | |

| |11.2.Signature | |

| | | |

| |11.3.Co-Guide (if any) | |

| |11.4.Signature | |

| | | |

| |11.5. Head of the Department |Dr. SHIVAKUMAR SWAMY |

| | |M. Pharm., Ph. D. |

| | |Principal & HOD |

| | |Mallige College Of Pharmacy, |

| |11.6.Signature |Bangalore, Karnataka |

| | |The present study is permitted to perform in the Pharmacology |

|12 |Remarks of the Principal |laboratory of our institution and the study protocol will be |

| | |approved by IAEC. |

| | | |

| |12.1. Signature |(Dr. Shivakumar Swamy) |

06 Brief resume of the intended work

Drug-drug interactions occur when one therapeutic agent either alters the concentration (pharmacokinetic interactions) or the biological effect of another agent (pharmacodynamic interactions). Pharmacokinetic drug-drug interactions can occur at the level of absorption, distribution, or clearance of the affected agent. Drugs are eliminated by metabolism. The microsomal reactions that have been studied the most involve cytochrome P (CYP) 450 family of enzymes, of which a few are responsible for the majority of metabolic reactions involving drugs. These include the isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A41. The concept of drug interaction is also extended to include; drug-drug interaction, drug-food interaction, drug-herbal interaction, drug-laboratory test interaction and drug-condition interaction2.

Metabolic drug interactions between drugs represent a major concern clinically for health care professionals and their patients. It has been estimated that some of the clinically significant drug-drug interactions may be the causes of adverse drug reactions (ADR) or causes of death. There are many reasons for so many ADRs. First, more drugs, and many combinations of drugs, are being used to treat patients than ever before. Secondly, a great number of prescriptions are filled out for one person. Finally, the rate of ADRs increases exponentially after a patient is on 4 or more medications. Efforts to reduce polypharmacy are important but for many patients, the number of medications cannot always be reduced without doing harm. That is why it is important to understand the basis for drug interactions. During the past few years a revolution has taken place in our understanding of drug interactions, mostly as a result of advances in the molecular biology of the CYP enzyme system. This will allow us to make the most appropriate choices in prescribing and avoiding preventable ADRs. Many drug interactions are a result of inhibition or induction of CYP enzymes3.

Omeprazole-

Omeprazole is the proton pump inhibitor (PPIs) which are substituted benzimidazole derivatives that inhibit the proton pump (H+/K+adenosine triphosphatase) in the parietal cells of the stomach. PPIs are the most potent medications available to reduce gastric acid secretion. Since their introduction in the late 1980s, these efficacious acid suppressants have rapidly assumed a major role for the treatment of acid-peptic disorders. Although these drugs are considered safe and have been approved for long-term use, some long-term safety concerns have been raised4.

Mechanism of action:

A. Omeprazole is a proton pump inhibitor that suppressors of gastric acid secretion are inhibitors of the gastric H+/K+- ATPase (proton pump).

B. Conversion of omeprazole to a sulfonamide in the canaliculi of the parietal cell. The sulfonamide interacts with sulfhydryl groups in the proton pump, there by irreversibly inhibiting its activity5.

Metabolism-

One of the reasons is the relatively high affinity of omeprazole for certain isoenzymes, or CYP isoforms, of the cytochrome P450 enzyme system. This system has a key function in hepatic oxidative drug Metabolism. Omeprazole is primarily metabolised via CYP2C19 and to a lesser extent by CYP3A46.Absorption is rapid, absolute bioavailability (compared to intravenous administration) is about 30 -40% at doses of 20- 40 mg. Protein Binding: 95%. Biotransformation: Hepatic. Half Life: 0.5-1 hour Dosage Forms: Oral tablets 7.

Clinical uses8

1. used in the treatment of peptic ulcer.

2. Gastro esophageal reflux disease (GERD).

3. Zollinger-Ellison syndrome.

Adverse reaction5:

Headaches

Nausea

Abdominal pain

Constipation

Flatulence and Diarrhoea

SERTRALINE-

Sertraline is an antidepressant and antipanic agent that is a potent and selective inhibitor of serotonin reuptake into the presynaptic terminal. Selective serotonin reuptake inhibitors (SSRIs) depress the firing of neurons in the raphe nucleus, which in turn may affect norepinephrine neurons of the locus ceruleus9. Sertraline is a potent and selective serotonin reuptake inhibitor in the central nervous system and is widely used to treat depression and obsessive-compulsive behaviour10.

Mechanism of action:

The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. The chronic administration of sertraline was found in animals to down-regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder11.

Metabolism-

N-demethylation is the main metabolic step in the biotransformation of sertraline12. CYP2C19 is probably a major enzyme contributing to the N-demethylation of sertraline because of its high affinity for sertraline and the marked difference in the enzyme kinetics of sertraline N-demethylation between human liver microsomes from different CYP2C19 genotypes. Previously, there has been little direct evidence regarding the specific CYP isoform that mediates the N-demethylation of sertraline in vivo10.Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethyl sertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethyl sertraline to be substantially less active than sertraline. Both sertraline and N-desmethyl sertraline undergo oxidative deamination and subsequent reduction,hydroxylation,glucuronide&conjugation11. In vitro protein binding studies performed with radio labeled 3H-sertraline showed

that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL11. At least five isoforms of CYP (2B6, 2C9, 2C19, 2D6, and 3A4) are involved in the metabolism of sertraline, but since the contribution of any individual isoform does not exceed 40% of the overall metabolism9.

Clinical uses11:

• It is used in the treatment of Major Depressive Disorder

• Obsessive Compulsive Disorder

• It is also used in the treatment of Social Anxiety Disorder.

• It is used in the treatment of Post traumatic Stress Disorder.

Adverse effects5:

1. Insomnia

2. Increased anxiety

3. Irritability

4. Decreased libido

5. Sexual side effects.

ENCLOSURE: I

6.1 NEED FOR STUDY

Depression is a serious illness that often leads to premature death. Suicide is one result of untreated depression, and is particularly common among the elderly. Among people age 75 and older, for example, 60 to 75 percent of suicides have diagnosable depression. Researchers at Harvard University and the University of Cincinnati found that more than 80 percent of 57 premature depression-related deaths were the result of worsened chronic conditions, smoking, alcohol abuse, poor self-care, or accidents. More than 80 percent of people who are depressed respond quickly and positively to treatment. However, in a survey of over 1,200 men and women from the U.S., nearly two out of three with depression reported waiting at least four years before seeking treatment. Common barriers to treatment include denial, shame, lack of money or insurance, and fear.

Women are more susceptible to depression:-Women are twice as likely as men to suffer from depression. Higher rates of depression in women are associated with both biological and social factors. Depression occurs most frequently in women ages 25 to 44, and peaks during childbearing years. Social factors such as stress from family and work responsibilities also increase the risk of depression in women. Because women have a longer life expectancy, the death of a spouse may also contribute to higher rates of depression in elderly women.

Men and women view depression differently, 43 percent of women identify depression as a health problem, compared to 32 percent of men. A larger proportion about 60 percent of men views depression as an emotional weakness, compared to 48percent of women. Because men are socially conditioned to hide their feelings, they are more likely to express their symptoms of depression through substance abuse, such as alcoholism, and antisocial behaviors13.

Some of antidepressants are norepinephrine reuptake inhibitors (NRIs),selective serotonin reuptake inhibitors(SSRIs), tricyclic antidepressants(TCAs), monoamine inhibitors(MAOs).TCAs are the major class of drugs to area the depression but a number of SSRIs were introduced from 1984-1997, all of the SSRIs show a clear improvement in safety margin compared to TCAs and are much safer in over dose and in clinical practice have affected a broad range of psychiatric, behavioral, and medical conditions. The SSRIs are effective in treating the major depression5.

Similarly peptic ulcer is a disorder requires a variety of relatively specific medical conditions in which injury by gastric acid(and activated pepsin) is thought to play an important role, these includes gastro esophageal reflux disease(GERD), Benign peptic ulcers of the stomach and duodenum, ulcers secondary use of NSAIDs and ulcer due to Zollinger-Ellison syndrome.

It appears that exposure of the involved tissues to acid is essential to the development of clinical symptoms of these diseases, control of gastric acidity is therefore necessary of therapy in these disorders. Since, of course considerable advances in understanding the pathogenesis and the treatment of acid-peptic conditions have occurred, including Helicobacter pylori and proton pump inhibitors. Currently there are several different proton pump inhibitors available for clinical use, omeprazole, lansoprazole, rabepazole etc. among these omeprazole is selectively inhibits gastric mucosal carbonic anhydrase, which may contribute to its acid suppressive properties14.

A possible protective effect of lithium against the occurrence of peptic ulcer complaints in manic-depressive patients, treated with lithium, was investigated. 167 manic-depressive patients, 91 in lithium treatment, 76 not in lithium treatment, were questioned about clinical symptoms of peptic ulcer. Thirteen of the lithium-treated and 23 of the non-lithium-treated patients reported symptoms of peptic ulcer. The difference was statistically significant. The hypothesis that lithium treatment reduces the frequency of symptoms of peptic ulcer in manic-depressive patients was thus confirmed. This observation says that both diseases might be present in same patient15.

Therefore both the disorders are managed clinically by administering numbers of drugs for long duration. In such a scenario, there is a possibility that one drug may alter the effects of other drugs. Cytochrome P450 is important for metabolism of many drugs. Although this class has more than 50 enzymes CYP1A2, 2C9, 2D6, 3A4, 2C19 etc and they metabolized number of drugs.

The recent in vitro study found that CYP2D6 and CYP3A4 appear not to be involved in the N-demethylation of sertraline and that CYP2C19 may be a major enzyme contributing to sertraline N-demethylation because of its high affinity for sertraline16.

CYP2C19: This isoenzyme also exhibits genetic polymorphism. It is involved in metabolism of a number of clinically important drugs e.g. omeprazole, diazepam, antidepressants and antimalarials3.

On the literature survey, it has been found that both the drugs are metabolised by common enzyme CYP2C19 16, 3. The omeprazole is an effective inhibitor of CYP2C19, therefore the effect of omeprazole on sertraline might be increases the side effect of sertraline3.

The study of the effect of omeprazole on pharmacokinetics and antidepressant activity of sertraline is very much important. Since both the drugs are metabolized by the common enzymes CYP2C19. Any alteration on the effect of sertraline is harmful to the patient. Since, it effects the mutual depression of the patient. The study on antidepressant activity will help to predict the extent of interaction whereas the study on pharmacokinetics parameters will help to predict the mechanism of action of drug interaction and also help to support the pharmacodynamic interaction.

The possibility of these two drugs to interact is by alteration at metabolism site. The literature survey reveals that the scientific studies have not been done to verify the interaction. So it is very much significant and justified to conduct experiment on animals to verify the drug-drug interaction between omeprazole and sertraline.

ENCLOSURE: II

6.2 REVIEW OF LITERATURE:-

A number of studies have reported that the coadministration of sertraline with TCA can increase the plasma concentrations of desipramine, imipramine and nortriptyline. The plasma levels of a co-administered CYP2D6 substrate can be increased by an average of 19% following administration of sertraline at 50 mg/day. The observation shows the increases in the plasma concentration of TCAs only weak inhibition of this system9.

Just two recent case reports give evidence for significant inhibition of clozapine’s metabolism by sertraline. Under 600 mg clozapine and 300 mg sertraline, the serum concentration of clozapine was 1300 ng/mL, and it decreased by 40% after discontinuation of sertraline (Pinninti & de Leon, 1997). A similar observation was described by Chong and co-workers (1997), who found that in a patient taking 175 mg clozapine, there was a 2.1-fold increase in clozapine serum concentration after addition of 50 mg sertraline, which disappeared after discontinuation of the SSRI12.

Patients in the sertraline plus alprazolam group also showed a significant reduction in performance on a computerized manual tracking test (i.e., psychomotor function). Sertraline, at a dose of 50 mg/day for 10 to 20 days, did not alter in vivo pharmacokinetics of alprazolam, a CYP3A4 substrate drug. A subsequent, randomized, controlled, in vivo study found a greater decrease in peak alprazolam concentration in patients who received sertraline 50 mg/day (but not 100 mg or 150 mg/day doses) than in those who received alprazolam only9.

A recent study in 11 patients with schizophrenia or schizoaffective disorder stabilized on risperidone therapy (4–6 mg/day) has demonstrated that an 8-week co-medication with sertraline, 50–100 mg/day, did not change significantly steady-state plasma concentrations of risperidone active fraction. However, in the two patients receiving the highest dose of sertraline, 150 mg/day, at week 8 total plasma risperidone concentrations were increased by 36% and 52%, respectively, as compared to baseline values, presumably because of a dose-dependent inhibition of CYP2D6-mediated 9-hydroxylation of risperidone17.

When sertraline was administered to patients maintained on methadone (a CYP3A4 substrate), a transient increase in methadone serum levels over the first 6 weeks of treatment was observed9.

With co-treatment with rifampicin (a potent CYP3A4 inducer), a 34-year-old man experienced a recurrence of generalized anxiety symptoms; when the sertraline was tapered, the patient experienced symptoms synonymous with SSRI withdrawal syndrome9.

sertraline has linear pharmacokinetics so that increases in dose lead to proportional increases in drug concentration. The half-life of sertraline is about 26 h so that it reaches a steady state in one week, according to the product monograph. Hypoglycemia associated with sertraline and co administration of oral hypoglycemics belonging to the sulphonylurea derivatives has rarely been reported18.

Some individuals are deficient in CYP2C19 and consequently metabolise omeprazole via alternative but less efficient pathways. In such slow metabolisers the serum concentration of omeprazole has been reported to reach levels that are on average fivefold higher and the area under the serum concentration versus time curve to be on average tenfold or even 20-fold greater than in normal rate metabolisers. At those concentration levels it is possible that omeprazole could effectively compete with phenprocoumon for binding sites on CYP2C9, thus resulting in competitive inhibition of phenprocoumon metabolism. This would explain the increased anticoagulant activity of phenprocoumon which was evident in the two described cases during co-medication with omeprazole6.

Omeprazole inhibits CYP2C19 (thereby decreasing the clearance of disulfiram, phenytoin and other drugs) and induces the expression of CYP1A2 (there by incearsing the clearance of imipramine, several antipsychotic drugs) 5. 2C19: This isoenzyme also exhibits genetic polymorphism. It is involved in metabolism of a number of clinically important drugs e.g. omeprazole, diazepam, antidepressants and antimalarials3. Above observation says that effect of omeprazole on disulfiram and other drugs might be decreases the clearance of those drugs3, 5.

1. in a double-blind crossover study 10 healthy males received placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin19.

A low dose of amlodipine (0.25mg/kg) combined with omeprazole (1mg/kg) also produced antiulcer activity. It is likely that amlodipine like other dihydropyridine calcium channel blocker may have antiulcer activity through multiple separate mechanisms, which are different from the famotidine or omeprazole. Hence simultaneous administration of low doses of amlodipine with famotidine or omeprazole may produce significant antiulcer activity20.

Dual drug therapy for eradication of helicobacter pylori is more beneficial in poor metabolisers of 2C19 than extensive metabolisers. This is because of decrease metabolism of omeprazole in poor metabolisers and inhibition of omeprazole metabolism by clarithromycin21.

ENCLOSURE: III

6.3 OBJECTIVE OF THE STUDY:

• To study the effect of omeprazole on pharmacokinetic parameters of sertraline in healthy albino rabbits.

• To study the possible interactions of omeprazole on anti-depressant activity of sertraline in healthy Albino wistar rats.

• To suggest the alterations in the dose and frequency of administration of sertraline, if necessary.

ENCLOSURE: IV

MATERIALS:

7.1 Source of data

a) The work is aimed to generate data from the experiments to be conducted at pharmacology laboratory of our institution. Albino rats and rabbits will be used for this purpose, and they will be obtain from animal house of Mallige College of Pharmacy, #71 Silvepura, Chikkabanavara Post, and Bangalore-560090. Ph: 080 32970763.

The study is divided into two parts:

• Study the effect of omeprazole treatment on pharmacokinetic parameters of sertraline in healthy Albino rabbits.

• Study the effect of omeprazole treatment on antidepressant activity of sertraline in healthy Albino wistar rats.

ENCLOSURE: V

7.2 Method of collection of data

I Study of effect of omeprazole on pharmacokinetic parameters of sertraline in albino rabbits

The four healthy albino rabbits will be treated with sertraline (20mg/kg, p.o). The concentration of the sertraline in blood at different time interval is measured by HPLC22.

In this method, the estimation of sertraline is carried out using a reversed phase C18 column (Grace smart RP-18), mobile phase (Acetonitrile/0.25 M potassium phosphate (pH2.7) 30:70v/v) and UV detection at a wavelength of 235 nm. Flow rate maintained at 1.0 ml/min.

In the second part of experiment, omeprazole (4mg/kg,p.o) is administered to the same group of animals once daily for one week after the gap of 15 days. On the 8th day, the sertraline (20mg/kg, p.o) is administered and the concentration of sertraline in blood at different time interval will be measured. The data obtained will be subjected to Ramkin software to obtain the following parameters (doses of two drugs have selected depending on previous experimental studies on animals).

• tmax (Time of peak plasma concentration)

• tt1/2 (Terminal half life)

• Cmax (Peak plasma concentration)

• AUC (Area under curve)

• AUMC (Area under movement curve)

• MRT (Mean residential time)

II. Effect of omeprazole treatment on anti-depressant activity of sertraline:

The effect of omeprazole treatment on anti-depressant activity of sertraline is studied using two animal models:

I. Despair swim model.

II. Serotonin syndrome in rats.

I. Despair swim test23:-

Six male albino rats weighing between 160-180 gm. are selected and forced to swim inside in a vertical Plexiglas cylinder (height: 40cm, diameter: 18cm, containing 15cm of water maintained at 25oC) and total duration of immobility is measured during a 5min test. An animal is judged to be immobile whenever it remains floating passively in the water in a slightly hunched but up right position, its nose just above the surface.

The rats were administered with sertraline (20mg/kg, p.o) and the duration of immobility is recorded at different time interval. The same group of animals are administered after the gap of 15 days with omeprazole (4mg/kg, p.o) daily once for one week. On the 8th day, sertraline (20mg/kg, p.o) is administered and the test is repeated.

II. Serotonin syndrome in albino rats23:-

Compounds which stimulate serotonin receptors cause behavioral changes in rats which is called serotonin syndrome. The behavioral change is measured in albino rats at different time interval. Six albino rats weighing between 180-210g are selected and administrated with sertraline (20mg/kg, p.o) and behavioral change is scored at different time interval. After the gap of 15 days, the same animals are treated with omeprazole (4mg/kg, p.o) once daily for one week. On 8th day sertraline (20mg/kg, p.o) is administered and the test is repeated.

Experimental design:

|SL.NO. | METHODS |NO. OF ANIMALS |

|I. |Pharmacokinetic study |4 Albino rabbits. |

|II. |Pharmacodynamic study | |

| |(Anti-depressant) | |

|1. |Despair swim test. |6 Male Albino wistar rats. |

| | | |

|2. |Serotonin syndrome in rats |6 Male Albino wistar rats. |

Statistical analysis:

Data are reported as mean ± SEM and Annova one way tests is used for the significance.

ENCLOSURE:VI

3. Does the study require any investigation or interventions to be conducted on patients or other humans and animals? If so please describe briefly.

The proposed study requires the investigation on albino rats and rabbits for the pharmacokinetic and anti-depressant activity.

4. Has ethical clearance been obtained from your institution in case of 7.3?

The present study protocol is approved from Institutional Animal Ethical Committee.

ENCLOSURE: VII

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Jepsen PW,  Jensen E,  Pienge P,  Rafaelsen OJ, Peptic ulcer complaints in lithium-treated and non-lithium-treated manic-depressive patients.2007;67(5):358-360.

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16. Joshua Kantrowitz, Leslie Citrome Paliperidone: the evidence of its therapeutic value in schizophrenia, Plasma risperidone concentrations during combined treatment with sertraline. 2008; 2(4):261–271.

Takhar J, Williamson P, Hypoglycemia associated with high doses of sertraline and sulphonylurea compound in a noninsulin-dependent diabetes mellitus patient. Can J Clin Pharmacol. 1999 Spring;6(1):12-4.

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18. AL Bhave, JD Bhatt, KG Hemavathi, Antiulcer effect of amlodipine and its interaction with H2 blocker and proton pump inhibitor in pylorus ligated rats. Research paper 2006; 38(6):403-407.

19. Futura T, Ohashi K, Kobayashi K, Iida I, Yoshida H, Shirai N et al. Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans. Clin Pharmacol Ther 1999; 66(3):265-74.

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21. Gerhard. H Vogel. Drug discovery and evaluation, Pharmacological Assays. Springer-Verlag, Berlin Heidelberg. 2002; 573:559-561.

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