摘要
目的:考察消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体CYP450酶7种亚型CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4/5的体外抑制作用。方法:消癌平注射液等4种抗肿瘤中药注射剂分别与7种CYP450酶亚型对应的混合探针药物在人肝微粒体中共同孵育,采用液相色谱-串联质谱(LC-MS/MS)法同时测定这7种探针药物的代谢产物:对乙酰氨基酚、羟基安非他酮、去甲阿莫地喹、4-羟基双氯芬酸、4-羟基美芬妥英、右啡烷和1-羟基咪达唑仑的浓度,分别代表CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4/5的活性,其对CYP450酶亚型的抑制程度以IC50值表示。结果:在体外人肝微粒体孵育体系中,消癌平注射液对CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19和CYP3A4/5的IC50值分别为0.51%、1.34%、1.42%、0.93%、1.09%和0.75%,艾迪注射液对CYP2C8的IC50值为0.21%;消癌平注射液对CYP2D6的IC50值为2.58%,艾迪注射液对CYP2B6、CYP2C9、CYP2C19和CYP3A4/5的IC50值分别为13.24%、16.31%、4.27%和3.73%,华蟾素注射液对CYP1A2、CYP2B6、CYP2C8和CYP2D6的IC50值分别为3.50%、28.01%、20.32%和32.59%,康艾注射液对CYP1A2、CYP2B6、CYP2C8、CYP2D6和CYP3A4/5的IC50值分别为2.55%、15.32%、1.44%、1.72%和3.99%,均高于各自的日用药量浓度;在测定浓度范围内,艾迪注射液对CYP1A2和CYP2D6,华蟾素注射液对CYP2C9、CYP2C19和CYP3A4/5,康艾注射液对CYP2C9和CYP2C19的活性抑制率均小于50%。结论:在体外,正常剂量下,消癌平注射液对人CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19和CYP3A4/5,艾迪注射液体对人CYP2C8均有明显抑制作用;消癌平注射液对CYP2D6,艾迪注射液对CYP2B6、CYP2C9、CYP2C19和CYP3A4/5,华蟾素注射液对CYP1A2、CYP2B6、CYP2C8和CYP2D6,康艾注射液对CYP1A2、CYP2B6、CYP2C8、CYP2D6和CYP3A4/5,均无明显抑制作用;艾迪注射液对CYP1A2和CYP2D6,华蟾素注射液对CYP2C9、CYP2C19和CYP3A4/5,康艾注射液对CYP2C9和CYP2C19,均无抑制作用。
AIM： To evaluate the inhibition of 4 anti-tumor traditional Chinese medicine injections on activities of 7 main cytochrome P450s CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 in human liver microsome in vitro. METHODS： 4 antitumor traditional Chinese medicine injections were incubated with human liver microsomes in the presence of seven probe substrates of CYP450 isoforms, respectively. Using LC-MS/ MS method simultaneous quantification of 7 probe substrate-derived metabolites acetaminophen（CYPiA2 ）, hydroxy-bupropin （CYP2B6）, n-desethyl-amodiaquine （CYP2C8）, 4′-hydroxydiclofenac （CYP2C9）, 4′-hydroxy-mephenytoin （CYP2C19 ）, de xtrorphan （CYP2D6） and 1-hydroxy-midazolam（CYP3A） to determine the activity of 7 CYP450 isoforms. The inhibitory effects were evaluated with half maximal inhibitory concentration （IC50） values. RESULTS. IC50 value of Xiao-Ai-Ping injection on CYP1A2, CYP2B6, CYP2CS, CYP2C9, CYP2C19, and CYP3A4/5 was 0.51%, 1.34%, 1.42%, 0.93%, 1.09%, and 0.75%, respectively. IC50 value of Ai-Di injection on CYP2C8 was 0.21%. IC20 value of Xiao-Ai-Ping injection on CYP2D6 was 2.58%; IC50 value of Ai-Di injection on CYP2B6, CYP2Cg, CYP2C19, and CYP3A4/5 was 13.24%, 16,31%, 4.27%, and 3.73%, respectively; IC50 value of Hua-Chan-Su injection on CYP1A2, CYP2B6, CYP2C8, and ZYP2D6 was 3.50%, 28.01%, 20.32%, and32.59 %, respectively; IC50 value of Kang-Ai in jection on CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP3A4/5 was 2.55%, 15.32%, 1.44%, 1.72%, and 3.99%, respctively, ICso values of them were exceeded their daily-dose concentrations, totally. The activity inhibition rates of Ai-Di injection on CYP1A2 and CYP2D6 ; Hua-Chan-Su injection on CYP2C9, CYP2C19 and CYP3A4/5; Kang-Ai injection on CYP2C9 and CYP2C19, were less than 50% within their concentration rangs of determinations. CONCLUSION. In vitro, Xiao-Ai-Ping injection and Ai-Di injection show significant inhibitory effect on CYP1A2, CYP2B6, CYP2CS, CYP2C9, CYP2C19, CYP3A4/5 and CYP2C8, respectively, under normal dosage. Xiao-Ai-Ping injection, Ai-Di injection, Hua- Chan-Su injection and Kang-Ai injection show minor inhibitory effect on CYP2D6; CYP2B6, CYP2C9, CYP2C19, CYP3A4/5; CYP1A2, CYP2B6, CYP2CS, CYP2D6 and CYP1A2, CYP2B6, CYP2C8, CYP2D6, CYP3A4/5, respectively. Ai-Di injection, Hua-Chan-Su injection and Kang-Ai injection don＇t show inhibitory effect on CYP1A2, CYP2D6 ; CYP2C9, CYP2C19, CYP3A4/5 and CYP2C9, CYP2C19, respectively.
出处
《中国临床药理学与治疗学》
CAS
CSCD
2014年第5期522-527,共6页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
上海市医院协会科研基金201002029
关键词
中药注射液
人肝微粒体
细胞色素P450酶
抑制作用
药物相互作用
traditional Chinese medicine injection
human liver microsomes
cytochromeP450, CYP
inhibition
herb-drug interaction
