In a study on the time
In a study on the time course of a mechanism-based inactivation of CYP3A by HIV protease inhibitors, Katzenmaier et al.  reported that the suppression of CYP3A activity continued for threedays after the discontinuation of ritonavir. In the present study, the CYP3A activity on day 28 after a seven-day washout period increased, but the activity was still lower than at baseline (63–76% of the baseline levels on day 0). Ochiai et al.  reported that the elimination half-life was 7.1±5.0h for ethinylestradiol and 27.6±4.6h for levonorgestrel in healthy women after the administration of the OC. Suppression of CYP3A activity was observed to continue even after elimination of the drug from the body. The effect of a mechanism-based inhibitor was long-lasting, and at least sevendays of washout were required to return to the baseline level.
Gorski et al.  evaluated the contribution of CYP3A inhibition on the interaction between midazolam and clarithromycin as a mechanism-based inhibitor and reported that higher baseline activity of CYP3A results in a greater inhibition with clarithromycin because the higher baseline activity results in higher formation of a metabolite intermediate-enzyme (CYP3A) complex. In the present study, subject 1 had the highest baseline activity of CYP3A and exhibited the highest inhibition (64%), but subject 4 had the lowest baseline activity and did not exhibit the smallest inhibition. As shown in Fig. 3A–D and Table 1, the average CLm(6β) values on day 21 (0.60–1.23mL/min) suppressed by the OC in four women were extremely low compared with the normal range (1.5–3.5mL/min) obtained in our previous study. We therefore need to pay attention to the subjects who concomitantly use a CYP3A substrate with a narrow therapeutic range during treatment with OCs regardless of their baseline levels of CYP3A. The endogenous dopamine-2 receptor antagonist 6β-hydroxylation clearance is the safest and simplest method of all phenotyping procedures to sequentially follow the in vivo enzyme activity in women during OC treatment because the administration of a probe drug is not required. This method is applicable to the evaluation of the inhibition of CYP3A by other OCs containing gestodene, 3-ketodesogestrel, medroxyprogesterone, desogestrel, norethisterone, and cyproterone. Further investigation will be required to conduct a statistical analysis of the inhibitory effects of oral contraceptives on the CYP3A activity in vivo.
Conclusion The present study was undertaken to evaluate the time course of 6β-hydroxylation clearance of endogenous cortisol (CLm(6β)) as a new index for phenotyping the in vivo CYP3A activity in four women after the sequential administration of an OC containing ethinylestradiol and levonorgestrel. The clearances (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 inhibitory effects of levonorgestrel, a weak inhibitor of CYP3A, on the in vivo CYP3A activity were clearly demonstrated by the 6β-hydroxylation clearance of endogenous cortisol. The inhibition of CYP3A activity by the OC over the 21-day period was 43–64%, which is a statistically significant decrease. The results presented here should provide important information on the inhibitory effect of OCs on the CYP3A activities involved in the metabolism of a number of drugs with a narrow therapeutic range in women. The present method can safely be used for predicting the individual drug metabolism and dispositions in various patients because it does not require the administration of a probe drug.
Introduction Polyphenols are aromatic molecules that contain multiple phenolic hydroxyl groups and are components of plant pigments with a bitter flavor. Polyphenols have been reported to be useful in anti-oxidative (Boots et al., 2008, Nakai et al., 2003) and anti-obesity (Ikarashi et al., 2011a, Ikarashi et al., 2011b) treatments, and are currently used in functional foods. Representative polyphenols include green tea polyphenols (GP), apple polyphenols, and wine polyphenols. GP are used worldwide for their varied pharmacological effects.