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.
Publication types
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Randomized Controlled Trial
MeSH terms
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Adult
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Arylamine N-Acetyltransferase / metabolism*
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Caffeine / administration & dosage
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Caffeine / pharmacokinetics
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Contraceptives, Oral / administration & dosage
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Contraceptives, Oral / pharmacokinetics*
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Cross-Over Studies
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Dextromethorphan / administration & dosage
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Dextromethorphan / pharmacokinetics
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Drug Combinations
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Drug Interactions
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Ethinyl Estradiol / administration & dosage
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Ethinyl Estradiol / pharmacokinetics*
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Female
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Genotype
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Humans
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Midazolam / administration & dosage
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Midazolam / pharmacokinetics
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Norgestrel / administration & dosage
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Norgestrel / analogs & derivatives*
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Norgestrel / pharmacokinetics
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Omeprazole / administration & dosage
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Omeprazole / pharmacokinetics
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Therapeutic Equivalency
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Vitamin K / administration & dosage
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Vitamin K / pharmacokinetics
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Warfarin / administration & dosage
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Warfarin / pharmacokinetics
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Xanthine Oxidase / metabolism
Substances
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Contraceptives, Oral
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Drug Combinations
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norgestimate, ethinyl estradiol drug combination
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Vitamin K
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Caffeine
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Norgestrel
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Ethinyl Estradiol
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Warfarin
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Dextromethorphan
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Cytochrome P-450 Enzyme System
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Xanthine Oxidase
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Arylamine N-Acetyltransferase
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NAT2 protein, human
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Omeprazole
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Midazolam