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  • CYP A is involved in the metabolism of approximately


    CYP3A is involved in the metabolism of approximately 50% of all drugs that are currently prescribed to patients [1], [15], [16]. Marked interindividual variabilitity of the catalytic function for metabolizing CYP3A substrates has been demonstrated with variability exceeding 20-fold [1]. Levonorgestrel has been used at a very low daily dose as one of the most widely prescribed contraceptive progestins. Levonorgestrel has a weak ability to inhibit CYP3A activity in in vitro studies [17], [18], [19]. On the other hand, several previous in vivo studies have produced conflicting results for evaluating the effect of OCs on the metabolism of CYP3A substrates. The in vivo inhibition of CYP3A activity by OCs has been judged from the decreased AUC of a CYP3A metabolite of nifedipine [12] or the increased clearance of 6α-methylprednisolone as a CYP3A substrate [11], whereas inhibition has not been observed by markers of CYP3A activity, such as the urinary ratios of 6β-hydroxycortisol/cortisol (6β-OHF/F) [20] and dextromethorphan/3-methoxymorphinan [21]. The major problem is that probe drugs, or the markers employed, are not specific for phenotyping CYP3A activity in vivo; therefore, these markers might be influenced by other factors such as the metabolism by enzymes other than CYP3A and/or the renal clearance of the substrates. In addition, the ability to inhibit CYP3A activities by levonorgestrel might be too weak to detect decreased activities of CYP3A in vivo. It is still unclear when and how the activity of CYP3A changes during OC treatment in women. We have previously reported evidence for the validity of 6β-hydroxylation clearance of endogenous Lamivudine (CLm(6β)) as a new index for in vivo CYP3A phenotyping in humans [22], [23]. The inhibitory effects of clarithromycin on in vivo CYP3A activity have clearly been demonstrated by the 6β-hydroxylation clearance (CLm(6β)), but not by a conventional index, the urinary ratio 6β-OHF/F [23]. Peng et al. also evaluated the inhibitory effects of itraconazole on in vivo CYP3A activity in humans by analyzing the cortisol and cortisone 6β-hydroxylation clearance [24]. The purpose of this study was to examine whether changes in the in vivo activity caused by levonorgestrel, a weak inhibitor of CYP3A, can be detected by the 6β-hydroxylation clearance of endogenous cortisol (CLm(6β)) as an index for in vivo CYP3A phenotyping. The present study was undertaken to evaluate the time course of in vivo CYP3A activity in four healthy women after sequential administration of an OC with ethinylestradiol and levonorgestrel using CLm(6β). The present study also followed the time course of the serum concentrations of endogenous estradiol and progesterone as well as CLm(6β) every 2h from 11:00 to 17:00 on days 0 and 28 or from 9:00 to 17:00 on days 1, 2, and 21. The method is the safest and simplest phenotyping procedure for sequentially following the in vivo enzyme activity throughout the day, week, and month, because the administration of a probe drug is not required. Our technique can also avoid potential physiological changes that may be caused by administration of a probe drug.
    Discussion Synthetic estrogens and progesterones (progestins) containing an acetylenic functional group are mechanism-based inhibitors of CYP3A enzyme in humans [3], [17], [19], [30]. The reactive intermediates derived from the acetylene group at C-17 of the steroidal skeleton bind to the protein of the P450 enzymes, leading to irreversible or reversible inactivation of the enzyme [31]. Guengerich [17] reported that the ability of gestodene or desogestrel to inhibit nifedipine oxidation by CYP3A in human liver microsomes is approximately 85% and 55%, respectively, whereas the effect of levonorgestrel is less than ∼20%, indicating that the inhibition of CYP3A activity depends on the type of progestins. Laine et al. [19] performed in vitro studies to evaluate the inhibitory effects of several progestins on CYP3A activity in human liver microsomes with CYP3A-mediated sulfoxidation of R-omeprazole as a substrate. They rank-ordered the progestins according to their inhibitory potency, and the order was gestodene>3-ketodesogestrel>medroxyprogesterone>desogestrel>norethisterone>levonorgestrel. Back et al. [18] also obtained similar in vitro results on the inhibition of progestins on CYP3A activity involved in the metabolism of cyclosporine as a substrate (gestodene>3-ketodesogestrel>norethisterone>levonorgestrel). The progestin with the highest inhibitory potency tested in vitro was gestodene, whereas levonorgestrel was a weak inhibitor of CYP3A in vitro.