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目的:评价HPPH在体外对大鼠及人肝微粒CYP450酶的6种亚型酶活性的影响,预测使用HPPH可能出现的药物相互作用。方法:将注射用HPPH与CYP450酶的6种亚型的特异性探针底物非那西汀(CYP1A2)、甲苯磺丁脲(CYP2C9)、S-美芬妥因(CYP2C19)、右美沙芬(CYP2D6)、氯唑沙宗(CYP2E1)、咪达唑仑(CYP3A4)和睾酮(CYP3A4)与大鼠及人肝微粒进行孵育反应,采用HPLC-MS/MS法测定对应的7种代谢产物(对乙酰氨基酚、羟基甲苯磺丁脲、4-羟基美芬妥因、O-去甲基右美沙芬、6-羟基氯唑沙宗、1′-羟基咪达唑仑、6β-羟基睾酮)的浓度。结果:在本实验条件下,HPPH浓度为1.00~50.00μmol·L-1时,未发现其对大鼠的CYP1A2、CYP2C9、CYP2D6、CYP2E1、CYP3A4产生抑制作用。在本实验条件下,HPPH浓度为0.50~10.00μmol·L-1时,未发现其对人CYP1A2产生抑制作用;但对人CYP2C9、CYP2C19、CYP2D6、CYP2E1均存在抑制作用;对人CYP3A4,对底物咪达唑仑存在抑制作用,对底物睾酮未发现抑制作用。结论:HPPH对CYP450酶的抑制作用存在种属差异,在人体内HPPH与CYP450酶作用有待体内实验进一步证明。
OBJECTIVE: To evaluate the effect of HPPH on the activities of 6 subtypes of CYP450 enzymes in rats and human liver in vitro, and to predict possible drug interactions with HPPH. Methods: The specific probe substrates of phenytoin (CYP1A2), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), CYP2E1, CYP3A4 and CYP3A4 were incubated with rat and human liver micro-particles. The corresponding 7 metabolites were detected by HPLC-MS / MS Acetaminophen, hydroxytolbutamide, 4-hydroxymephenytoin, O-demethyl dextromethorphan, 6-hydroxychlorzoxazone, 1’- hydroxy midazolam, 6 beta-hydroxytestosterone) concentration. Results: Under the experimental conditions, no inhibition of CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 was found when the concentration of HPPH was 1.00-50.00 μmol·L-1. Under the conditions of this experiment, no inhibition of human CYP1A2 was found when the concentration of HPPH was between 0.50 and 10.00 μmol·L-1, but inhibited the activity of human CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Substance midazolam inhibition, no inhibition of substrate testosterone. Conclusion: The inhibitory effects of HPPH on CYP450 enzymes are different from each other. The in vivo effects of HPPH and CYP450 enzymes in human body are further evidenced.