title: The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Sarich
authors.forename: T
authors.initials: T
authors.lastname: Kalhorn
authors.forename: S
authors.initials: S
authors.lastname: Magee
authors.forename: F
authors.initials: F
authors.lastname: al-Sayegh
authors.forename: S
authors.initials: S
authors.lastname: Adams
authors.forename: J
authors.initials: J
authors.lastname: Slattery
authors.forename: J
authors.initials: J
authors.lastname: Goldstein
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.forename: J
authors.initials: J
authors.lastname: Wright
mesh_terms: 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
chemical_list: D018712:Analgesics, Non-Narcotic; D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; D000082:Acetaminophen; D009853:Omeprazole; D008617:Mephenytoin