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; pp. 1413 - 1421
• 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: Oxford, UK Blackwell Publishing Ltd 01-12-2005; SAGE Publications; Sage Publications, Inc
• Subjects: Adult; Arylamine N-Acetyltransferase - metabolism; Caffeine - administration & dosage; Caffeine - pharmacokinetics; cocktail; Contraceptives, Oral - administration & dosage; Contraceptives, Oral - pharmacokinetics; Cross-Over Studies; Cytochrome P-450; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Dextromethorphan - administration & dosage; Dextromethorphan - pharmacokinetics; Drug Interactions; Drug metabolism; drug-metabolizing enzymes; 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; Oral contraceptives; Therapeutic Equivalency; Vitamin K - administration & dosage; Vitamin K - pharmacokinetics; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Xanthine Oxidase - metabolism
• ISSN: 0091-2700; 1552-4604
• 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 Kwith and without a triphasic oral contraceptive (ethinyl estradiol 35 μg) 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.