沙利度胺在大鼠炎症性肠病模型中药动学研究

Research of pharmacokinetics of thalidomide in SD rats with inflammatory bowel disease

目的研究沙利度胺在炎症性肠病(inflammatory bowel disease,IBD)SD大鼠模型中的胃肠道吸收过程,对比疾病状态与正常状态下沙利度胺口服吸收的差异,为沙利度胺用药安全性和有效性提供基础。方法使用三硝基苯磺酸造模法建立IBD大鼠模型,连续干预6 d,每天观察、记录大鼠一般状态与疾病活动指数。设置健康大鼠沙利度胺口服组为对照,同时对IBD模型组大鼠于造模6 d后口服给予沙利度胺,给药剂量均为10 mg·kg^(-1),采集不同时间点的大鼠血液样本。经大体形态学及组织病理学综合评估,选取IBD造模成功大鼠样本,采用经验证的高效液相色谱-质谱联用法测定沙利度胺血药浓度,计算药动学参数并与健康大鼠对比。结果IBD模型组体质量明显低于空白对照组,疾病活动指数、结肠形态评分与组织病理学评分均明显高于空白对照组,造模成功率为62.5%。药代动力学结果显示,IBD组大鼠C_(max)(P<0.05)与AUC(P<0.01)相较健康大鼠均升高了2~3倍,而T_(1/2)、T_(max)、MRT等参数无明显差异。结论相较于正常大鼠,在炎症性肠病模型中,大鼠口服沙利度胺的吸收速度与程度显著提高,这可能为临床口服沙利度胺用于IBD的治疗提出新的考量。

Aim To investigate the absorption of thalidomide in inflammatory bowel disease(IBD)SD rats compared with healthy rats to provide a basis for the safety and efficacy of thalidomide in clinical practice.Method The IBD rat model was induced by the 2,4,6-trinitrobenzene sulfonic acid,by which the rats were continuously intervened for six days.The general state and disease activity index of the rats were recorded every day.The rats in IBD group after modeling and control group were administered with thalidomide at a dose of 10 mg·kg^(-1).The blood sample of the rats was collected at different time points.After a comprehensive evaluation of morphological and histopathological results,the samples of rats with IBD were determined by proven high performance liquid chromatography-mass spectrometry,and the pharmacokinetic parameters were calculated and compared with the healthy rats.Results The body weight of rats in IBD group was obviously lower than that in control group and the disease activity index,score of colonic macroscopic morphous and histopathology were obviously higher than those in control group.The success rate of modeling was 62.5%.The pharmacokinetic results showed that the C_(max)(P<0.05)and AUC(P<0.01)of the IBD group both increased by 2 to 3 times,but there was no significant difference in t_(1/2),T_(max),MRT and other parameters.Conclusions The rate and extent of oral thalidomide absorption of rats in the model of inflammatory bowel disease significantly increase compared to those of healthy rats,which may provide new considerations for clinical practice of thalidomide in the treatment of IBD.