他克莫司在溃疡性结肠炎模型大鼠体内的药代动力学研究

Pharmacokinetics of Tacrolimus in Ulcerative Colitis Model Rats

目的:考察他克莫司(FK506)在葡聚糖硫酸钠(DSS)诱导的溃疡性结肠炎(UC)模型大鼠体内的药代动力学特点。方法:将12只大鼠随机分为UC组和正常组各6只,UC组给予5%DSS连续自由饮用7 d诱导建立UC模型,第8天分别给予两组大鼠灌胃FK5061 mg/kg,于给药前和给药后不同时间点采血,测定FK506血药浓度,比较分析两组大鼠主要药代动力学参数。结果:与正常组相比,UC组体内的FK506暴露强度增加,AUC_(0-t)增加了44.06%,半衰期延长了1.85 h(近50%),体内滞留时间(MRT_(0-∞))延长了37.0%,清除率下降了32.25%(P均<0.05)。结论:FK506在大鼠体内的药代动力学会受到UC的影响,导致FK506代谢下降,半衰期延长,暴露强度增加,可能与UC影响P糖蛋白和CYP3A酶活性有关。

Objective:To probe into the pharmacokinetic characteristics of tacrolimus(FK506)in dextran sodium sulfate(DSS)-induced ulcerative colitis(UC)in rats.Methods:Twelve rats were randomly divided into the UC group and the normal group,with 6 cases in each group.The UC group was given 5%DSS for 7 d to induce the UC model.On the 8^(th) d,two groups were given FK506 for 1 mg/kg by gavage.Blood samples were collected at different time points before and after administration to determine the concentration of FK506,and the main pharmacokinetic parameters of two groups were compared and analyzed.Results:Compared with the normal group,the exposure intensity of FK506 in the UC group increased,the AUC_(0-t) increased by 44.06%,the half-life was prolonged by 1.85 h(nearly 50%),the in vivo retention time(MRT_(0-∞))was prolonged by 37.0%and the drug clearance rate decreased by 32.25%(P<0.05).Conclusion:The pharmacokinetics of FK506 in rats is affected by UC status,resulting in decreased FK506 metabolism,prolonged half-life,and increased exposure intensity,which may be related to the effect of UC status on P-glycoprotein and CYP3A enzyme activities.