夫西地酸及其羧酸酯前药在大鼠体内的药动学研究

摘要

本文旨在测定夫西地酸(Fusidic Acid,FA)及其羧酸酯前药F1和F2在大鼠体内的药代动力学特征,为基于ADME特性改善的化学结构修饰提供实验依据.将健康雄性SD大鼠随机分为3组,分别灌胃给予FA、F1和F2的CMC -Na混悬液,给药剂量均为50 mg/kg,分别在给药前和给药后不同时刻采集血样,在体内F1和F2迅速转化为FA,经乙酸乙酯萃取后HPLC法测定血浆中FA的浓度,应用DAS2.0软件计算非房室模型药动学参数,采用两独立样本比较的非参数检验进行组间差异的显著性分析.结果表明,血浆中FA的浓度在0.1~6 μg/mL范围内与色谱峰面积呈良好线性关系(r=0.9998),定量下限为0.1 μg/mL,回收率大于80%,日内和日间精密度(RSD)均在15% 以内,该方法灵敏度高、专属性好,符合生物样品的分析要求.血浆中FA的达峰时间Tmax分别为4、12和4 h,T1/2分别为11.4、16.9和10.3 h,AUC0-t分别为33.24、78.48、36.41 μg/(mL·h),T1/2和AUC0-t的组间差异显著(p<0.05),F1、F2的前药特征明显,其中F1的吸收程度更高,具有更高的生物利用度.%The aim of this study is to investigate pharmacokinetic characteristics of fusidic acid (FA) and its car-boxylic ester pro-drugs F1 and F2 in rats to provide experimental evidence for structure modification on the basis of the improvement of ADME properties. Healthy male SD rats are randomly divided into three groups with six rats in each group,then are orally administered with FA, F1 and F2 at a single dosage of 50 mg/kg (all calculate as FA),respectively. F1 and F2 are rapidly converted to FA in vivo. An HPLC method is established to determinate FA in rat plasma after extraction with ethyl acetate. Non-compartmental estimation of pharmacokinetic parameters is carried out by using the software of DAS(version 2.0) according to plasma concentration versus time curves. The results show that the HPLC method has good linearity in the concentration range of 0.1-6 μg/mL(r=0.999 8) with a lower limit of quantification of 0.1 μg/mL. The precision, accuracy, extraction recovery and stability are consistent with the requirements of measurement. The time to peak concentration of FA is 4 h,12 h and 4 h, T1/2 11.4 h,16.9 h and 10.3 h,AUC0-t33.24 μg/mL/h,78.48 μg/mL/h and 36.41 μg/mL/h,respectively. There are significant differences between groups in the pharmacokinetics among T1/2and AUC0-t(p<0.05). F1 and F2 show an abvious pro-drug feature,but the former has higher plasma concentration and bioavailability.