羟基喜树碱的代谢与CYP450的相关性研究

Correlation between Hydroxycamptothecin Metabolism and CYP450 Activity

目的：研究羟基喜树碱（HCPT）在体外小鼠肝微粒体中对 CYP450活性的影响，为临床合理联合用药提供参考。方法：在小鼠体外肝微粒体中分别加入六种亚型酶的探针药物对乙酰氨基酚、非那西丁、双氯芬酸钠、睾酮、酒石酸美托洛尔、奥美拉唑和羟基喜树碱溶液，在优化的孵育体系下温孵。用 HPLC 法测定各空白对照组和羟基喜树碱溶液中各探针药物代谢产物的浓度并比较代谢率的差异，以评价羟基喜树碱对各亚型酶活性的影响。结果：在代谢反应过程中，在50~200μmol＆#183;L-1内，羟基喜树碱的浓度与孵育体系中 CYP3A4的特异性底物睾酮、CYP2E1的特异性底物对乙酰氨基酚的剩余药量呈正比例关系，且具显著性差异（P＜0.05），与其他四种探针药物的剩余药量无明显的浓度依存关系（P＞0.05）。结论：HCPT 在肝微粒体的代谢反应过程中受代谢酶 CYP3A4和 CYP2E1的作用，竞争性地抑制了睾酮和对乙酰氨基酚在肝微粒体中的代谢。

Objective： To investigate the effect of hydroxycamptothecin （HCPT） on CYP450 in rat liver microsomes in vitro, providing reference for clinical rational use of drug combination therapy. Methods：Probe drugs of testosterone, tartrate, phenacetin, diclofenac sodium, acetaminophen, and omeprazole as well as HCPT were added to incubation systems of rat liver microsomes in vitro, the concentrations of the probe drugs in blank or with HCPT were determined by HPLC after incubation and the differences of metabolic rates were compared to evaluate the effects of HCPT on the activities of the six CYP450 subtypes. Results： L-HCPT at 50～200 μmol·L-1 inhibited the metabolism of testosterone and acetaminophen and had no effect on the metabolism of metoprolol tartrate, phenacetin, diclofenac sodium and omeprazole. Conclusion： We concluded that HCPT is affected by CYP3A4 and CYP2E1 in the metabolic process and competitively inhibited the metabolism of testosterone and acetaminophen in liver microsomes.