The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin.
Omeprazole, a widely used and potent gastric proton pump inhibitor, induces cytochrome P450 (CYP) 1A2 in humans. Induction is most pronounced in slow metabolizers of S-mephenytoin because CYP2C19 (S-mephenytoin hydroxylase) is responsible for the elimination of omeprazole. Acetaminophen (INN, paracetamol), a widely used and effective analgesic and antipyretic agent, causes serious hepatic and renal toxicity at high doses by conversion of acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) through CYP1A2, CYP2E1, and CYP3A4. This study evaluated whether omeprazole pretreatment in five rapid and five slow metabolizers of S-mephenytoin could increase thioether (an estimate of NAPQI production) metabolite formation from acetaminophen. The results of this study show that, despite induction of CYP1A2 activity in slow metabolizers (a 75% increase in plasma clearance of caffeine), the formation of NAPQI from acetaminophen was not increased after 7 days of omeprazole administration (40 mg/day). This suggests that induction of CYP1A2 activity by omeprazole is unlikely to increase the risk of acetaminophen hepatotoxicity.
Sarich
T
T
Department of Pharmacology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Kalhorn
T
T
Magee
S
S
al-Sayegh
F
F
Adams
S
S
Slattery
J
J
Goldstein
J
J
Nelson
S
S
Wright
J
J
D000082:Acetaminophen / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics*; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology*; D010641:Phenotype; D012016:Reference Values
D018712:Analgesics, Non-Narcotic; D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; D000082:Acetaminophen; D009853:Omeprazole; D008617:Mephenytoin