title: 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.
abstract: 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 2h 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 21days. The average CLm(6β) levels that were suppressed by the OC in four women were extremely low (0.60-1.23mL/min) compared with the normal CLm(6β) range (1.5-3.5mL/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.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address: sibasaki@toyaku.ac.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shibasaki
authors.affiliation: School of Nursing, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo 162-8666, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kuroiwa
authors.affiliation: School of Nursing, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo 162-8666, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Uchikura
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Tsuboyama
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Akitomo
authors.initials: A
authors.lastname: Yokokawa
authors.affiliation: School of Nursing, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo 162-8666, Japan.
authors.forename: Miyoko
authors.initials: M
authors.lastname: Kume
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Furuta
mesh_terms: D000328:Adult; D003276:Contraceptives, Oral / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D057075:Enzyme Assays / Q000379:methods*; D004958:Estradiol / Q000097:blood; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006900:Hydroxylation / Q000187:drug effects; D016912:Levonorgestrel / Q000494:pharmacology*; D010641:Phenotype; D011374:Progesterone / Q000097:blood
chemical_list: D003276:Contraceptives, Oral; D065692:Cytochrome P-450 CYP3A Inhibitors; D004997:Ethinyl Estradiol; D011374:Progesterone; D004958:Estradiol; D016912:Levonorgestrel; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone
keywords: CYP3A inhibitors; Cortisol 6β-hydroxylation clearance; Drug–drug interaction; In vivo CYP3A activity; Oral contraceptives