紫杉烷类药物对SD大鼠CYP3A1作用效应的研究

 目的研究紫杉烷类抗癌药紫杉醇和多西紫杉醇对Sprague-Dawley(SD)大鼠肝细胞CYP3A1活性的作用。方法本实验将15只雄性SD大鼠随机分为空白对照组(尾静脉注射给予生理盐水,每只1mL,每日1次,连续3d)、地塞米松诱导组(灌胃给予地塞米松,100mg·kg^-1·d^-1,连续3d)、酮康唑抑制组(腹腔注射给予酮康唑,50mg·kg^-1·d^-1,连续3d)、紫杉醇实验组(尾静脉注射给予紫杉醇,6.7mg·kg^-1·d^-1,连续3d)、多西紫杉醇实验组(尾静脉注射给予多西紫杉醇,30mg·kg^-1·d^-1,连续3d)。采用HPLC检测以睾酮为探针药物经大鼠肝微粒体温孵后转化的代谢产物6β-羟基睾酮的生成速率以评价各组间CYP3A1酶的活性。结果空白对照组、地塞米松诱导组、酮康唑抑制组、紫杉醇实验组、多西紫杉醇实验组6β-羟基睾酮的生成速率分别为(643.1±6.0),(2671.1±225.7),(78.3±4.8),(724.8±36.6)和(489.3±70.6)pmol·mg(pro)^-1·min^-1;数据经SPSS16.0统计软件分析,表明紫杉醇组和多西紫杉醇组6β-羟基睾酮的生成速率与地塞米松诱导组、酮康唑抑制组的差异均有极显著性(P<0.01),与生理盐水空白对照组的差异均无显著性(P>0.05)。结论紫杉醇和多西紫杉醇对大鼠肝细胞CYP3A1酶活性无诱导或抑制作用。

Effects of Taxanes on Activity of CYP3A1 in SD Rats

OBJECTIVE To investigate the effects of taxanes including paclitaxel and docetaxel on activity of liver microsome cytochrome P450 3A1 in SD rats.METHODS 15 Male SD rats were randomly grouped and treated with physiological saline(NS,1 mL/each rat,iv,3 d),dexamethasone(DEX,100 mg·kg^-1·d^-1,po,3 d),ketoconazole(KET,50 mg·kg^-1·d^-1,ip,3 d),paclitaxel(PAC,6.7 mg·kg^-1·d^-1,iv,3 d) and docetaxel(DOC,30 mg·kg^-1·d^-1,iv,3 d),respectively.A HPLC-UV method was established and validated to determine the productive velocity of metabolite(6β-hydroxyl-testosterone,6β-OHT) of testosterone(as substrate of CYP3A1) and to measure the activity of CYP3A1.RESULTS The productive rates of 6β-OHT of NS,DEX,KET,PAC and DOC groups were(643.1±6.0),(2 671.1±225.7),(78.3±4.8),(724.8±36.6) and(489.3±70.6) pmol·mg(pro)^-1·min^-1.There are significant differences between PAC and DOC groups compared with dexamethasone group and ketoconazole group,but there were no significant difference between taxanes groups and the control group.CONCLUSION Paclitaxel and docetaxel had no induce or inhibition effect on the enzymic activity of CYP3A1 in rats.