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The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity
Author(s) -
Belle Donna J.,
Callaghan John T.,
Gorski J. Christopher,
Maya Juan F.,
Mousa Omiema,
Wrighton Steven A.,
Hall Stephen D.
Publication year - 2002
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.0306-5251.2001.01521.x
Subject(s) - midazolam , cyp3a , pharmacokinetics , medicine , oral administration , pharmacodynamics , norgestrel , concomitant , levonorgestrel , urine , pharmacology , population , cytochrome p450 , metabolism , environmental health , family planning , research methodology , sedation
Aims To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. Methods In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg −1 ) and oral 15 N 3 ‐midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral ™ (50 µg ethinyloestradiol/500 µg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15 N 3 ‐midazolam and metabolites by liquid chromatography‐mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. Results Moderate (% CV 26–46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,∞) iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,∞) oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral ™ for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half‐life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations ( r = −0.936). Conclusions Administration of Ovral ™ for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.