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  • As discussed in the introduction many

    2019-09-05

    As discussed in the introduction, many pregnant women take medications such as nifedipine and indinavir, which are considerably metabolized by CYP3A [26]. Previous reports have also shown increased CYP3A activity following pregnancy [7], [9], which is consistent with our results. However, previous studies involved the use of probe drugs to assess CYP3A activity, which may have limitations in application for clinical use. In contrast, we used a relatively less invasive approach to assess CYP3A activity. We observed no differences in CYP3A activity based on the pregnancy trimester when the activity of CYP3A was measured using the 4β-OH-cholesterol/cholesterol ratio. Each of the steroids quantified in this study showed a similar increasing trend with pregnancy trimesters, but there was no difference in the calculated ratios. Based on this result, we speculate that the capacity of CYP3A in the H-Lys(Ac)-OH.HCl of substrates is high enough that significant changes in the endogenous parental substrate might result in increased production of its metabolites and further affect interpretation using metabolic markers of CYP3A activity. The quantified metabolic markers in this study are known to reflect hepatic CYP3A activity, though both hepatic and intestinal CYP3A activity are responsible for metabolism of orally administered drugs. A previous study suggested that intestinal CYP3A4 activity (as indicated by daily oral doses of carbamazepine) may influence the formation of 4β-OH-cholesterol [27]. Therefore, further studies are still necessary to evaluate the involvement of intestinal CYP3A4 in the formation of 4β-OH-cholesterol.
    Introduction Extracts of Tripterygium wilfordii Hook F (TWHF) have been used for centuries as the drug of choice for treatment of rheumatoid arthritis, a disease of autoimmune dysfunction, in traditional Chinese medicine (Bao and Dai, 2011, Tao et al., 2002). Triptolide (TP), a structurally distinct diterpene triepoxide isolated from TWHF, has been identified as the primary active ingredient responsible for its biological activities since 1970s (Kupchan et al., 1972). TP has been reported to possess a wide variety of pharmacological activities, including anti-inflammatory, immunosuppressive, anti-cystogenesis and antitumor activities (Leuenroth et al., 2007, Liu, 2011). Nevertheless, the application of TP in the clinical settings has been largely restricted because of its narrow therapeutic window and severe toxicity to digestive, reproductive and hematopoietic systems (Liu et al., 2010, Liu et al., 2011, Ni et al., 2008). For this reason, diverse structure modifications of TP are under investigation for improved safety (Zhou et al., 2012). In vitro studies indicated that TP is converted into mono-hydroxylated metabolites by cytochrome P450s, in which CYP3A4 is the primary isoform responsible for the hydroxylation of TP (Li et al., 2008). Pretreatment with dexamethasone, a CYP3A inducer, significantly increases the metabolism of TP in male rat liver microsomes and decreases TP-induced hepatotoxicity in rats (Ye et al., 2010). Moreover, knockout of hepatic P450 reductase results in markedly increased blood and tissue levels of TP, as well as apparently exacerbated toxicity caused by TP in mice (Xue et al., 2011). Thus, hepatic P450s, especially CYP3A, play a critical role in the metabolic detoxification of TP. Glycyrrhizin (GL) is the principal bioactive component of licorice, which has been extensively used in traditional Chinese medicine for the treatment of various inflammatory diseases (Eisenbrand, 2006) or as a tonifying herbal medicine (Zhang and Ye, 2009). Recent studies have also found that combined administration of licorice/GL and TWHF/TP showed potentiated efficacy and reduced toxicity on treatment of rheumatoid arthritis in rat collagen-induced arthritis model (YS et al., 2008, Zhang et al., 2007) as well as in clinical applications (YS et al., 2006). GL has been reported to selectively influence the activity of CYPs (Hu et al., 1999, Paolini et al., 1998). Experiments in healthy volunteers demonstrated that GL induced CYP3A4-dependent sulfoxidation of omeprazole (Tu et al., 2010). Several pharmacokinetic studies also suggested that GL could significantly alter the metabolic fate of multiple co-administered drugs in rats (Lin et al., 2009, Matta et al., 2009, Mu et al., 2006).