Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5-Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94.2% and 64.2% of the metabolism, respectively. Pharmacokinetics studies were conducted in male SD rats following administration of triptolide or (5R)-5-hydroxytriptolide (0.4 mg/kg, po). The plasma exposure to triptolide and (5R)-5-hydroxytriptolide in the rats was significantly increased when co-administered with the CYP3a inhibitor ritonavir (30 mg/kg, po) with the values of AUC_0-∞ (area under the plasma concentration-time curve from time zero extrapolated to infinity) being increased by 6.84 and 1.83 times, respectively. When pretreated with the CYP3a inducer dexamethasone (50 mg·kg^-1·d^-1, for 3 d), the AUC_0-∞ values of triptolide and (5R)-5-hydroxytriptolide were decreased by 85.4% and 91.4%, respectively. These results suggest that both triptolide and (5R)-5-hydroxytriptolide are sensitive substrates of CYP3a. Because of their narrow therapeutic windows, clinical drug-drug interaction studies should be carried out to ensure their clinical medication safety and efficacy.

中文翻译：

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CYP3A4诱导剂和抑制剂强烈影响雷公藤甲素及其衍生物在大鼠中的药代动力学。

雷公藤内酯醇是雷公藤雷公藤钩F的最有效成分，可用于治疗类风湿关节炎。（5R）-5-羟基雷公藤内酯醇是雷公藤内酯醇的羟基化衍生物，具有降低的毒性。为了研究这两种化合物的代谢酶以及与酶诱导剂或抑制剂的药物相互作用，进行了一系列的体外和体内实验。使用重组人细胞色素P450酶的体外研究表明，细胞色素P450 3A4（CYP3A4）在雷公藤内酯醇和（5R）-5-羟基雷公藤内酯醇的代谢中占主导地位，分别占代谢的94.2％和64.2％。在给予雷公藤甲素或（5R）-5-羟基雷公藤内酯（0.4 mg / kg，口服）后，在雄性SD大鼠中进行了药代动力学研究。_0-∞（从时间零外推到无穷大的血浆浓度-时间曲线下的面积）分别增加了6.84和1.83倍。用CYP3a诱导剂地塞米松（50 mg·kg ^-1 ·d ^-1，持续3 d）预处理时，雷公藤甲素和（5R）-5-羟基雷公藤甲素的AUC0 _-∞值分别降低85.4％和91.4％ 。这些结果表明雷公藤甲素和（5R）-5-羟基雷公藤甲素都是CYP3a的敏感底物。由于其治疗窗口狭窄，应进行临床药物相互作用研究，以确保其临床药物安全性和有效性。