title: Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail.
abstract: The effects of a common oral contraceptive preparation on the activity of 7 drug-metabolizing enzymes were investigated using the validated Cooperstown 5+1 Cocktail. In a randomized crossover fashion, 10 premenopausal women received caffeine, dextromethorphan, omeprazole, intravenous midazolam, and warfarin + vitamin K with and without a triphasic oral contraceptive (ethinyl estradiol 35 microg) and varying doses of daily norgestimate (0.18, 0.215, and 0.25 mg). Bioequivalence testing showed nonequivalence in drug versus no-drug treatment on the activity of drug-metabolizing enzymes (as reflected by metabolite ratios following probe drug administration); the activity of CYP1A2, CYP2C19, and NAT-2 decreased following the oral contraceptive, whereas the activity of CYP2C9 and CYP2D6 increased. No effects on xanthine oxidase or hepatic CYP3A were seen. Application of a non-parametric statistical testing approach revealed a significant difference only for CYP1A2 and CYP2C19. This triphasic oral contraceptive may have a clinically significant effect on the activity of some drug-metabolizing enzymes.
authors.affiliation: Department of Medicine, Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Shelepova
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Victory
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rowland
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Edward
authors.initials: E
authors.lastname: Sellers
authors.forename: Gregory
authors.initials: G
authors.lastname: Kearns
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
mesh_terms: D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D009644:Norgestrel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D014812:Vitamin K / Q000008:administration & dosage / Q000493:pharmacokinetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D003276:Contraceptives, Oral; D004338:Drug Combinations; C109079:norgestimate, ethinyl estradiol drug combination; D014812:Vitamin K; D002110:Caffeine; D009644:Norgestrel; D004997:Ethinyl Estradiol; D014859:Warfarin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D009853:Omeprazole; D008874:Midazolam