Benzodiazepine Metabolism and Pharmacokinetics ...

Benzodiazepine Metabolism and Pharmacokinetics Complied by Mena Raouf, Pharm.D. Candidate, 2016, reviewed and edited by Dr. Jeffrey Fudin

Benzodiazepines that undergo Phase I metabolism

Desmethyldiazepam

Diazepam

Temazepam

Alprazolam

CYP3A4

-hydroxy-alprazolam

Oxazepam

Clonazepam

CYP3A4 7-aminoclonazepam

NAT2

7-acetamido clonazepam

Midazolam

CYP3A4

1- hydroxy-midazolam

4- hydroxy-midazolam

Demoxepam

Des-methyl-diazepam

Chlordiazepoxide (pro-drug)

Nor-chlordiazepoxide

CYP 3A4

Oxazepam

Benzodiazepines that undergo Phase II metabolism (LOT) UGT2B15

Lorazepam Oxazepam

Lorazepam-glucuronide

UGT2B15 UGT1A9 UGT2B7

Oxazepam-glucuronide

Temazepam

Oxazepam Temazepam-glucuronide

Table 1: Metabolism and Elimination of select benzodiazepines

Parent Drug

Approximat e Equivalent Dose

Time to Peak Plasma Level following oral administrati on (Hours)

Metabolic pathway

Enzymes

Eliminat ion halflife of Parent Drug (Hours)

Metabolites

Detection window in Urine Drug Screening (Days)

Benzodiazepine Anxiolytics

Diazepam

5mg

0.5-2

Alprazolam 0.5mg

1-2

Demethylation CYP 2C19 20-80 Hydroxylation CYP 3A4

Hydroxylation

CYP 3A4 12-15 hours

Desmethyldiazepam (major) Temazepam (minor) Oxazepam (minor)

-hydroxyalprazolam

10-30 days 6,8 5 days

Clonazepam 0.25mg

1-4

Nitroreduction Acetylation

CYP 3A4 30-40 NAT2

7-amino-clonazepam 5 days

Oxazepam

15mg

2-4

Temazepam 15mg

1-2

Lorazepam

1mg

2-4

Chlordiazepoxi 25mg

1-4

de

Conjugation Conjugation Conjugation

UGT2B15 UGT1A9 UGT2B7 UGT2B7 UGT2B15 2C19 3A4 UGT2B15

5-20 3-13 10-20

N-demethylation CYP3A4 6.6-28 Hydroxylation

Oxazepamglucuronide

Oxazepam

5 days 1-4 days

Lorazepam glucuronide

5 days

Desmethylchlordiaze poxide demoxepam Desmethyldiazepam (active) Oxazepam (active)

5-30 days6,8

Midazolam

5mg

Benzodiazepine Sedative Hypnotics

Hydroxylation CYP 3A4 1-4

4- Hydroxymidazolam

1- Hydroxymidazolam

0.5-2 days

Triazolam

0.25mg

Flurazepam 15mg

Estazolam Quazepam

1-2mg 10mg

15-30 minutes

30-60 minutes

Hydroxylation oxidation

1.5-2 hours Oxidation

1-2 hours

Oxidation

Non Benzodiazepine Sedative Hypnotics "Z-Drugs"

CYP3A4 1.5-5.5 4-hydroxytriazolam 7-15 hours.

hydroxytriazolam CYP3A4 2.3 hours Ndesalkylflurazepam 4-16 days

CYP3A4

CYP3A4, CYP2C9, and CYP2C19

10-24 hours

39-73 hours

Flurazepamaldehyde 1-oxo-estazolam 4-hydroxy-estazolam

N-desalkyl-2oxoquazepam

1-4 days 2-4 days

2-oxoquazepam

Zolpidem

5-10mg

Zaleplon

5-10mg

Eszopiclone 1mg

30 minutes

15-30 minutes

15-45 minutes

Oxidation

Oxidation

Oxidation Demethylation

CYP 3A4 , CYP2C9, CYP2D6, CYP2C19 Aldehyde Oxidase (major)

CYP3A4 CYP 3A4 (major) CYP2E1

2.5 hours

1 hour

6-7 hours

Zolpidem carboxylic acid

5-oxo-zaleplon Desethylzaleplon 5-oxodesethylzaleplon

(S)desmethylzopiclone

(S)-zopiclone-Noxide

1-3 days

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