加味佛手散胶囊体外体内对大鼠肝脏CYP450酶活性的影响  

Effects of Jiawei Foshou San capsule on rat hepatic cytochrome P450 enzymes in vitro and in vivo

作　　者：尚芳红[1] 俸珊[2] 陈乾[2] 陈先进[2] 徐晓玉 SHANG Fang-hong;FENG Shan;CHEN Qian;CHEN Xian-jin;XU Xiao-yu(Chongqing Academy of Chinese Materia Medica,Chongqing 400065,China;College of Pharmaceutical Sciencesand Chinese Medicine,Southwest University,Chongqing 400715,China)

机构地区：[1]重庆市中药研究院,重庆400065 [2]西南大学药学院中医药学院,重庆400715

出　　处：《药学学报》2019年第6期1101-1107,共7页Acta Pharmaceutica Sinica

基　　金：科技部重大新药创制专项资助项目(2014ZX09304-306-04);重庆市基础研究与前沿探索项目(cstc2018jcyjAX0669);重庆市科研机构绩效激励引导专项资助项目(cstc2018jxjl-jbky120002)

摘　　要：考察加味佛手散胶囊在体外和体内对大鼠肝微粒体CYP1A2、CYP2C6、CYP2D2、CYP2E1、CYP3A1/2亚酶活性的影响,为临床提供药物代谢动力学以及与其他药物合用时的参考。采用肝微粒体体外孵育"鸡尾酒"法,LC-MS/MS法测定代谢产物,评价各受试组CYP同工酶活性,HE染色观察用药前后肝组织病理变化。在体外,最高抑制浓度3 200 mg·L^-1加味佛手散胶囊对大鼠肝微粒体CYP2D2、CYP2E1、CYP3A1/2的IC50分别为229.3、361.9和274.6 mg·L^-1。在体内,与空白对照组比较,180 mg·kg^-1·d^-1的加味佛手散胶囊组CYP1A2、CYP2C6和CYP3A1/2的酶活性显著升高(P<0.01)。用药后加味佛手散胶囊组有炎细胞浸润,但病理变化程度明显较延胡索乙素组轻微。体外抑制体内诱导实验提示加味佛手散胶囊临床使用如果与其他经CYP2D2、CYP2E1酶代谢的药物同时使用,可能使该药作用效果增强,作用时间延长,联合用药时应适当减少用药剂量;如果与其他经CYP1A2、CYP2C6酶代谢的药物同时使用,则可能使该药作用效果减弱,作用时间缩短,联合用药时应适当增加用药剂量。另外,延胡索乙素与阿魏酸、川芎嗪联合使用后,能显著降低延胡索乙素对大鼠肝脏的毒性作用。本研究中动物实验方案获得西南大学药学院实验动物管理与使用委员会的批准。This study aimed to evaluate the effects of Jiawei Foshou San capsule(JWFSSC)on CYP1 A2,CYP2 C6,CYP2 D2,CYP2 E1 and CYP3 A1/2 enzyme activities in rat liver microsomes in vitro and in vivo,and to provide pharmacokinetic data for its combined use with other medicines.After incubating liver microsomes with a cocktail of probe drugs,the metabolites were quantitated with LC-MS/MS to assess the CYP enzyme activity.The hepatic pathological changes were evaluated by histology after hematoxylin and eosin(HE)staining.With the dose range up to 3 200 mg·L^-1,the IC50 of JWFSSC for CYP2 D2,CYP2 E1 and CYP3 A1/2 in vitro was 229.3 mg·L^-1,361.9 mg·L^-1 and 274.6 mg·L^-1 respectively.Compared with the vehicle control group,the enzyme activities of CYP1 A2,CYP2 C6 and CYP3 A1/2 showed a significant increase in animals given JWFSSC 180 mg·kg^-1·d^-1(P<0.01).Based on histology,several pathological changes were observed in JWFSSC groups:there was less inflammatory infiltration compared to the tetrahydropalmatine(THP)group.These results of inhibition in vitro and induction in vivo suggest a strengthened efficacy and a prolonged effective time of drugs metabolized by CYP2 D2 and CYP2 E1 enzymes when combined with JWFSSC in use.The dosage of parent drugs should be appropriately reduced when used in combination with JWFSSC.However,if a drug is metabolized by CYP1 A2 and CYP2 C6 when used in combination with JWFSSC,the effect of the drug is likely reduced and the dosage should be increased appropriately.In addition,the combination of ferulic acid(FA),ligustrazine(LZ)and THP can significantly reduce the toxicity of THP in rat livers.In this study,the program of animal testing had been approved by Committee on the management and usage of experimental animal in the College of Pharmaceutical Sciences,Southwest University.

关 键 词：加味佛手散胶囊 细胞色素CYP450 延胡索乙素 肝毒性 药物相互作用 药物代谢动力学 

分 类 号：R969[医药卫生—药理学]