State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2018 Aug;39(8):1386-1392. doi: 10.1038/aps.2017.170. Epub 2017 Dec 28.
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 (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·d, for 3 d), the AUC 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.
雷公藤红素是雷公藤的最有效成分，用于治疗类风湿性关节炎。(5R)-5-羟基雷公藤红素是雷公藤红素的羟基化衍生物，毒性降低。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）在雷公藤红素和(5R)-5-羟基雷公藤红素的代谢中占主导地位，分别占代谢的 94.2%和 64.2%。雄性 SD 大鼠给予雷公藤红素或(5R)-5-羟基雷公藤红素（0.4mg/kg，po）后进行药代动力学研究。当与 CYP3a 抑制剂利托那韦（30mg/kg，po）联合给药时，大鼠血浆中雷公藤红素和(5R)-5-羟基雷公藤红素的暴露量显著增加，AUC（从零时外推至无穷大的血浆浓度-时间曲线下面积）分别增加了 6.84 倍和 1.83 倍。当用 CYP3a 诱导剂地塞米松（50mg·kg·d，连续 3d）预处理时，雷公藤红素和(5R)-5-羟基雷公藤红素的 AUC 值分别降低了 85.4%和 91.4%。这些结果表明，雷公藤红素和(5R)-5-羟基雷公藤红素均为 CYP3a 的敏感底物。由于它们的治疗窗较窄，应进行临床药物相互作用研究，以确保其临床用药的安全性和疗效。
