环孢素在溃疡性结肠炎模型大鼠体内的药物代谢动力学研究

Pharmacokinetics of Cyclosporine in Rats with Dextran Sulfate Sodium Induced Ulcerative Colitis

目的:探讨环孢素(CsA)在葡聚糖硫酸钠(DSS)诱导溃疡性结肠炎(UC)模型大鼠体内的药物代谢动力学(药动学)特征。方法:将12只SPF级SD大鼠按随机数表法分为UC模型组和正常对照组各6只,UC模型组大鼠给予5%DSS连续自由饮用7 d诱导建立UC模型,正常对照组大鼠正常饲养。第8天分别给予两组大鼠灌胃CsA 15 mg/kg,并于给药前和给药后不同时间点采血,测定CsA的血药浓度,比较两组大鼠主要药动学参数。结果:与正常对照组相比,UC模型组CsA的体内暴露强度增加,药时曲线下面积(AUC)增加35.69%,半衰期延长34.94%,体内滞留时间(MRT)延长23.17%,体内清除率下降28.00%(P均<0.05)。结论:CsA在大鼠体内的药动学会受到UC状态的影响而导致CsA吸收增加,代谢减慢,CsA体内的暴露强度增加,其具体作用机制还需要进一步研究。本研究结论可为CsA的安全用药研究提供参考。

Objective:To investigate the pharmacokinetics of cyclosporine(CsA)in rats with ulcerative colitis(UC)induced by sodium glucan sulfate(DSS).Methods:Twelve rats were randomly divided into two groups:the control group(normal feeding)and the UC group(5%DSS free drinking for 7 days to induce the UC model).On the 8day,rats in both groups were given CsA 15 mg/kg by gavage.Blood collection was performed before and after the administration,the plasma concentration was detected and the main pharmacokinetic parameters were compared between groups.Results:Compared with the control group,the exposure intensity of CsA in the UC group was significantly increased,the area under the curve(AUC)was increased significantly by 35.69%,the half-life was extended by 34.94%,the retention time(MRT)was also extended by 23.17%,and the drug elimination rate was decrease significantly by 28.00%(P<0.05).Conclusion:The pharmacokinetics of CsA in rats can be changed by UC disease status.Metabolism decline,half-life extension,and increased exposure intensity,may be related to the increased CsA absorption.This study provides references for the safe use of CsA in clinical.