猪囊性纤维化跨膜电导调节因子抑制剂A在小鼠体内的药动学与组织分布

Pharmacokinetics and Tissue Distribution of Porcine CFTR Inhibitor A in Mice

目的 pCFTRinh-A是猪CFTR特异的小分子抑制剂,研究其在小鼠体内的药动学及组织分布特点。方法按20 mg.kg-1腹腔注射给药,采用HPLC测定生物样品中pCFTRinh-A浓度。结果小鼠腹腔注射pCFTRinh-A后5 min即可测到药物存在,主要药动学参数:t1/2kα、t1/2α、t1/2β、tmax、AUC、ρmax和CL(s)分别为(2.089±0.481),(21.576±0.761),(155.424±28.723),(11.32±1.006)min、(489.055±12.538)μg.min.mL-1、(7.461±0.143)μg.mL-1和(0.041±0.001)L.min-1。药动学特征表现为:pCFTRinh-A在小鼠体内吸收分布迅速,达峰时间快,消除缓慢,生物利用度较高。药物分布具有一定组织分布特异性,主要分布于肝、肾、肺组织,其次为心、脾、肠组织,脑组织中分布最少。结论 pCFTRinh-A在小鼠体内药动学和组织分布特点的研究为建立人类囊性纤维化病变的大动物模型奠定基础。

OBJECTIVE To study the pharmacokinetics and tissue distribution of pCFTRinh-A in mice.METHODS 20 mg·kg^-1 pCFTRinh-A was given by intraperitoneal injection.HPLC method for the determination of pCFTRinh-A in plasma and tissues was established and applied to determine pCFTRinh-A in plasma and tissue samples.RESULTS The plasma concentration of pCFTRinh-A was found after 5 min of administration.The main pharmacokinetic parameters were as follows： t1/2ka（2.089±0.481） min,t1/2a（21.576±0.761） min,t1/2β（155.424±28.723） min,AUC（489.055±12.538） μg·min·mL^-1,tmax（11.32±1.006） min,ρmax（7.461±0.143） μg·mL^-1,CL（s）（0.041±0.001） L·min^-1.The absorption and distribution of pCFTRinh-A was quick while elimination was slow with high bioavailability.The distribution of pCFTRinh-A was high in liver,kidney and lung,while lower in heart,spleen and intestines and lowest in brain.CONCLUSION The pharmacokinetics and tissue-distribution characters of pCFTRinh-A will be helpful for building cystic fibrosis phenotype in large animals.