Use of endogenous cortisol 6β-hydroxylation clearance for phenotyping in vivo CYP3A activity in women after sequential administration of an oral contraceptive (OC) containing ethinylestradiol and levonorgestrel as weak CYP3A inhibitors

•Cortisol 6β-hydroxylation clearance phenotypes CYP3A activity inhibited by an OC. (84).•The inhibition of CYP3A activities was 43–64% by oral contraceptive treatment. (82).•It takes at least 7 days to return to CYP3A baseline activity after OC treatment. (84).

The present study was undertaken to evaluate the time courses of in vivo cytochrome P450 3A (CYP3A) inhibition in four healthy women after sequential administration of an oral contraceptive (OC) containing ethinylestradiol and levonorgestrel, using 6β-hydroxylation clearance of endogenous cortisol (CLm(6β)) as a new index for CYP3A phenotyping. The 6β-hydroxylation clearance (CLm(6β)) was followed every 2 h from 9:00 or 11:00 to 17:00 on days 0 (baseline), 1, 2, 21, and 28 during a single menstrual cycle. The serum concentrations of endogenous estradiol and progesterone were also measured. The time course data of CLm(6β) clearly demonstrated 43–64% inhibition of CYP3A activity in women taking a low daily dose of the OC for 21 days. The average CLm(6β) levels that were suppressed by the OC in four women were extremely low (0.60–1.23 mL/min) compared with the normal CLm(6β) range (1.5–3.5 mL/min) that was obtained from 49 healthy subjects in our previous study. The in vivo inhibitory potencies (43–64%) obtained in this study were stronger than expected from reported in vitro studies (∼20%). Furthermore, it would take at least seven days to return to the baseline activity of CYP3A after discontinuation of the OC. The results presented here should provide important information on the inhibitory effect of OC on the CYP3A activities in women, which are involved in the metabolism of a number of drugs with a narrow therapeutic range.

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