异丙酚在人肝微粒体中酶促动力学研究

Enzyme Kinetics Research of Propofol in Human Liver Microsomes

目的:研究异丙酚在人肝微粒体中的代谢。方法:高效液相色谱法测定孵育液中异丙酚的浓度。研究异丙酚的酶促动力学,推导出药物米氏常数(Km)和最大反应速度(Vmax);计算体外酶对药物的清除率(CLint)。同时观察CYP酶特异性抑制剂对异丙酚代谢的影响。结果:异丙酚在人肝微粒体中Km和Vmax分别为777.43μmol·L-1和172.41μmol·L-1·h-1·mg-1protein,CLint为0.22h-1·mg-1protein。CYP2B6特异性抑制剂氯吡格雷能够显著抑制异丙酚的代谢,而CYP2C9和CYP2C19特异性抑制剂对异丙酚代谢无显著影响。结论:异丙酚主要经CYP2B6代谢,CYP2B6酶抑制剂可能会抑制异丙酚的代谢,造成药效或毒性的增加。

Objective: To analyze the metabolism of propofol in human liver microsomes. Methods: An HPLC method was used to determine the concentration of propofol in the incubation fluid. Enzymatic dy-namics of propofol was also calculated to deduce the drug Michaelis constant (Km), the maximum reaction rate (Vmax) and the drug clearance (CLint) in vitro. Effects on the metabolism of propofol were observed with specific inhibitors on different kinds of CYP enzymes. Results: The Km and Vmax of propofol in hepatic mi-crosomes was 777.43μmol·L-1 and 172.41μmol·L-1·h-1·mg-1protein, respectively. The CLint was 0.22 h-1·mg-1protein. The specific inhibitor of CYP2B6 could decrease the metabolism of propofol, while CYP2C9 and CYP2C19 inhibitors could not influence the metabolism. Conclusion: Propofol is mainly metabolized by CYP2B6. When combined with CYP2B6 specific inhibitors, effect or toxicity of propofol would be enhanced.