奥美拉唑在葡聚糖硫酸钠诱导的溃疡性结肠炎大鼠肝肾肠微粒体中的代谢研究

目的：研究葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）模型大鼠不同病期肝、肾、肠微粒体中奥美拉唑（OME）代谢酶活性的变化。方法：DSS诱导UC急性期（UCA）和恢复期（UCR）大鼠模型。同时制备UCA、UCR以及正常对照（NOR）组大鼠的肝、肾、肠微粒体。将不同浓度的OME与微粒体共孵育，用LC/MS/MS检测样品中5-OH OME的生成量，比较OME在各组微粒体中的代谢活性。结果：连续饮用5% DSS 7 d，UCA和UCR组大鼠表现出明显的结肠炎症状。DSS停药后7 d，UCR组大鼠症状有所好转。UCA组肝微粒体中5-OH OME的生成速率低于NOR组，UCR组的生成速率恢复到正常水平。UCA组的CL_int与NOR组相比降低了45%。OME在3组大鼠肾和肠微粒体中的代谢活性无显著差异。结论：OME在肝微粒中的代谢会受到UC的影响而改变，可能会影响到OME在患者体内的药动学。

Metabolism of omeprazole in hepatic,renal and intestinal microsomes from rats with ulcerative colitis induced by dextran sulfate sodium

OBJECTIVE To study the metabolizing activities of omeprazole (OME) in microsomal proteins of liver (RLMs),kidney (RRMs) and intestine (RIMs) from rats at different statuses of ulcerative colitis (UC) induced by dextran sulfate sodium (DSS).METHODS The models of UC in acute (UCA) and recovery (UCR) phases were induced in rats by DSS (5% DSS in drinking water for 7 days for UCA and UCR groups,then DSS withdrawal for 7 days for UCR group).The RLMs,RRMs and RIMs were prepared simultaneously.The different concentrations of omeprazole were coincubated with microsomes,and formation of 5-OH OME was detected by LC/MS/MS.The metabolizing activities of OME in microsomes were compared between different groups.RESULTS After 7 days of DSS treatment,rats in UCA and UCR groups displayed typical ulcerative colitis like symptoms,and rats in UCR group recovered partially after DSS withdrawal for another 7 days.In RLMs,the formation rate of 5-OH OME was lower in UCA group than in NOR group,and recovered to normal level in UCR rats.The CL_int in UCA rats deceased by 45% compared with normal rats.The metabolizing activity of OME in RRMs and RIMs showed no significant difference between 3 groups.CONCLUSION The metabolizing activity of OME in liver microsomes can be changed by UC,which may lead to pharmacokinetics changes of OME in UC patients.