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  • br Materials and methods br

    2019-08-20


    Materials and methods
    Results
    Discussion TP has aroused extensive explorations because of its potent anti-inflammatory, immune-suppressive and antitumor activities. Notwithstanding these, TP has yet to enter Phase II clinical trials owing to its severe toxicity (Zhou et al., 2012). TP could induce amenorrhea in female rats (Liu et al., 2011) as well as sperm damage in males (Ni et al., 2008) at very low doses. Furthermore, previous studies in our laboratory showed that hepatotoxicity seemed to be one of the most severe adverse reactions of TP, demonstrated by both biochemical and morphological changes (Fu et al., 2011, Liu et al., 2010, Wang et al., 2013). Therefore, it is crucial to comprehensively understand the pharmacokinetic profiles of TP with the aim of improving its safety. Several pharmacokinetic and metabolic studies of TP in rats or rat liver microsomes have been reported, but most of them were focused on males only. (Liu et al., 2010) recently reported significant sex-specific toxicity of TP in rats, and ascribed it to the sex-differential hepatic metabolic activity, which has been validated only in rat liver microsomes. However, little is known about the differences of pharmacokinetics of TP between males and females in vivo. In the present study, the pharmacokinetic characteristics of TP were investigated on male and female rats. As shown in Fig. 1 and Table 2, the results demonstrated marked differences of pharmacokinetic profiles of TP between male and female rats, which are accordant with the previous study that a greater rate of TP metabolism was observed in male rat hepatic microsomes than in females (Liu et al., 2010). Greater exposure to TP in female rats indicated by the especially higher AUC∞ and Cmax may help explain why female rats are more susceptible to the toxicity of TP than male rats. Besides, small sexual differences of TP CNQX reviews indicated by almost the same value of Tmax as well as higher rate of TP elimination indicated by the higher value of CL/F in males suggested that male rats showed greater metabolic activity of TP than females in vivo, since TP was reported to be eliminated from the body mostly by metabolism (Shao et al., 2007). As mentioned above, hepatic P450s, in particular CYP3A, play a critical role in the metabolic clearance of TP. Thus, the difference in the expression and activity of CYP3A (whose main isoforms in rats are CYP3A1 and 3A2) in male and female rats would be responsible for greater TP exposure in females. For example, total hepatic CYP content and CYP3A1 mRNA level in females were about half of that in males (Asaoka et al., 2010), CYP3A2 is predominant in males (Waxman and O׳Connor, 2006), and a sex-specific metabolic pattern of TP in microsomes disappeared after pretreatment with anti-rat CYP3A2 antibody (Liu et al., 2010), all of which strongly suggest an important role of CYP3A2 in the gender-dependent metabolism of TP in rats. Numerous TP derivatives (Butler, 2008) and related formulations (Liu et al., 2005, Liu et al., 2008) have been explored for improved safety. Combined administration of TP and other chemical drugs (Ding et al., 2012, Li et al., 2012, Yang et al., 2011) is also under investigation for the purpose of reduced toxicity or synergistic therapeutic effect. In the current study, after pretreatment with GL, the pharmacokinetic parameters of TP in rats were significantly altered, confirming a drug–drug interaction between TP and GL. As demonstrated by the increased CL/F and decreased AUC∞, pretreatment with GL significantly accelerated the elimination of TP from the body, thus leading to less exposure to TP. In addition, pretreatment with GL reduced the Cmax of TP in male rats to half of that in control rats, indicating significant impact on the metabolism of TP in males than in females. However, specific mechanism remains to be determined. MDZ is recognized as a relatively specific CYP3A probe drug; decreased AUC of MDZ, increased AUC of its hydroxylated metabolite, OH-MDZ and increased ratio of AUC of OH-MDZ to MDZ are considered as biomarkers of induced CYP3A activity (Urva et al., 2013). As summarized in Table 5, pretreatment with GL significantly increased the AUC∞ of OH-MDZ and the ratio of AUC∞ of OH-MDZ to MDZ, suggesting that pretreatment with GL induces hepatic CYP3A activity in rats.