The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity.
OBJECTIVE
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 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral(50 microg ethinyloestradiol/500 microg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-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,infinity)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,infinity)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.
Belle
Donna J
DJ
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Callaghan
John T
JT
Gorski
J Christopher
JC
Maya
Juan F
JF
Mousa
Omiema
O
Wrighton
Steven A
SA
Hall
Stephen D
SD
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D016001:Confidence Intervals; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D019304:Ethinyl Estradiol-Norgestrel Combination / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
D003277:Contraceptives, Oral, Combined; D006993:Hypnotics and Sedatives; D019304:Ethinyl Estradiol-Norgestrel Combination; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam