Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail

• Published in: Journal of clinical pharmacology Vol. 45; no. 12; p. 1413
• Main Authors: Shelepova, Tatiana, Nafziger, Anne N, Victory, Jennifer, Kashuba, Angela D M, Rowland, Elizabeth, Zhang, Yanhua, Sellers, Edward, Kearns, Gregory, Leeder, J Steven, Gaedigk, Andrea, Bertino, Jr, Joseph S
• Format: Journal Article
• Language: English
• Published: England 01.12.2005
• Subjects: Adult; Arylamine N-Acetyltransferase - metabolism; Caffeine - administration & dosage; Caffeine - pharmacokinetics; Contraceptives, Oral - administration & dosage; Contraceptives, Oral - pharmacokinetics; Cross-Over Studies; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Dextromethorphan - administration & dosage; Dextromethorphan - pharmacokinetics; Drug Interactions; Ethinyl Estradiol - administration & dosage; Ethinyl Estradiol - pharmacokinetics; Female; Genotype; Humans; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Norgestrel - administration & dosage; Norgestrel - analogs & derivatives; Norgestrel - pharmacokinetics; Omeprazole - administration & dosage; Omeprazole - pharmacokinetics; Therapeutic Equivalency; Vitamin K - administration & dosage; Vitamin K - pharmacokinetics; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Xanthine Oxidase - metabolism
• ISSN: 0091-2700
• DOI: 10.1177/0091270005280851

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.