Impact of the Herbal Medicine <em>Sophora flavescens</em> on the Oral Pharmacokinetics of Indinavir in Rats: The Involvement of CYP3A and P-Glycoprotein

Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%–83% decrease in AUC0-∞ and 38%–78% reduction in Cmax. The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.苦参（Sophora flavescens）是一味传统中药材，可用于治疗胃肠道出血、皮肤病、热淋与病毒性肝炎。本研究以大鼠为实验模型，评估了苦参与艾滋病治疗用蛋白酶抑制剂茚地那韦（indinavir）之间的草药-药物相互作用。每日两次经口给予大鼠苦参提取物（0.158 g/kg或0.63 g/kg，灌胃）与茚地那韦（40 mg/kg，灌胃），连续给药7天后，血浆中茚地那韦浓度呈剂量依赖性下降，AUC₀-∞降低55%~83%，Cmax降低38%~78%。苦参给药组大鼠的CL/F（清除率/体循环可用剂量分数）升高最多达7.4倍。氧化苦参碱（oxymatrine）给药（45 mg/kg，灌胃）同样可降低茚地那韦的血浆浓度，而苦参提取物的乙酸乙酯组分则无此作用。苦参给药后，大鼠24小时尿中茚地那韦含量降低，而粪便中茚地那韦的占比升高。与对照组相比，多次给予苦参提取物可升高小肠与肝脏中P-糖蛋白（P-gp）的信使核糖核酸（mRNA）与蛋白表达水平。此外，苦参给药可升高小肠与肝脏中细胞色素P450 3A1（CYP3A1）的mRNA表达，但对细胞色素P450 3A2（CYP3A2）的表达影响较小。尽管苦参给药未改变CYP3A1与CYP3A2的蛋白水平，但苦参给药组大鼠的肝脏CYP3A活性显著升高。所有现有实验数据表明，多次联合给药后，苦参可降低血浆茚地那韦浓度，其潜在机制可能与增强肝脏CYP3A活性以及诱导小肠与肝脏中的P-gp表达有关。本动物研究有助于预测天然产物与口服制剂间的潜在相互作用，并可为人体试验前阐明相关作用机制提供参考依据。本研究结果提示，使用茚地那韦的患者应谨慎使用苦参提取物或苦参衍生制剂。