水飞蓟宾对索拉非尼在大鼠体内药动学的影响及机制研究

Effect and mechanism of silibinin on pharmacokinetics of sorafenib in rats

目的研究不同剂量水飞蓟宾对索拉非尼在大鼠体内药动学的影响并探究相关机制。方法雄性SD大鼠随机分为索拉非尼(100 mg/kg)组、低剂量(50 mg/kg)水飞蓟宾+索拉非尼(100 mg/kg)组和高剂量(100 mg/kg)水飞蓟宾+索拉非尼(100 mg/kg)组,每组6只,连续8 d ig空白溶剂或水飞蓟宾后ig索拉非尼,于不同时间点采集血样,测定血浆索拉非尼质量浓度。采用qRT-PCR检测大鼠肝组织中细胞色素P4503A1(cytochrome P4503A1,CYP3A1)、尿苷二磷酸葡萄糖醛酸转移酶1A7(UDP-glucuronosyltransferase 1A7,UGT1A7)和小肠组织中P-糖蛋白(P-glycoprotein,P-gp)和乳腺癌耐药蛋白(breast cancer resistance protein,BCRP)m RNA表达。结果50 mg/kg水飞蓟宾使索拉非尼的Cmax、AUC0~t和AUC0~∞分别增加了47.4%、57.1%和64.7%,100 mg/kg水飞蓟宾使索拉非尼的C_(max)、AUC_(0~t)和AUC_(0~∞)分别增加了47.6%、80.5%和79.8%;联合给药组小肠组织中P-gp和BCRP mRNA表达明显受到抑制(P<0.05),但肝组织中CYP3A1和UGT1A7mRNA表达没有变化。结论水飞蓟宾和索拉非尼联用存在药动学相互作用,可能会增加索拉非尼不良反应发生风险,临床联合使用时应加强监测,必要时调整给药剂量。

Objective To investigate the effect of silibinin on pharmacokinetics and mechanism of sorafenib in rats.Methods Male SD rats were randomly divided into sorafenib(100 mg/kg)group,low-dose silibinin(50 mg/kg)+sorafenib(100 mg/kg)group and high-dose silibinin(100 mg/kg)+sorafenib(100 mg/kg)group,with six rats in each group.After 8 d of ig blank solvent or silibinin,rats were ig sorafenib,blood samples were collected at different time points to determine the concentration of sorafenib in plasma.The mRNA expressions of cytochrome P4503A1(CYP3A1),UDP-glucuronosyltransferase 1A7(UGT1A7)in liver tissue and P-glycoprotein(P-gp),breast cancer resistance protein(BCRP)in small intestine tissue of rats were detected by qRT-PCR.Results Silibinin at dose of 50 mg/kg increased the C_(max),AUC_(0−t) and AUC_(0−∞) of sorafenib by 47.4%,57.1%and 64.7%respectively,while 100 mg/kg silibinin increased the C_(max),AUC_(0−t) and AUC_(0−∞) of sorafenib by 47.6%,80.5%and 77.5%respectively.The expressions of P-gp and BCRP mRNA in small intestine were obviously inhibited(P<0.05),but the expressions of CYP3A1 and UGT1A7 mRNA in liver tissue had no change.Conclusion There is a pharmacokinetic interaction between silibinin and sorafenib,which may increase the risk of adverse reactions of sorafenib.Monitoring should be strengthened in clinical combined use,and the dosage should be adjusted if necessary.