间尼索地平消旋体在大鼠血浆中的蛋白结合率及其肠吸收动力学研究

Study of Plasma Protein Binding Rate and Intestinal Absorption Kinetics of m-Nisoldipine Despinner in Rats

目的:研究间尼索地平消旋体在大鼠血浆中的蛋白结合率及其肠吸收动力学。方法:采用平衡透析法和高效液相色谱(HPLC)法测定尼索地平消旋体(0.2、0.5、1.0、2.0μg/ml)在大鼠血浆中的蛋白结合率,并计算白蛋白结合药物的表观最大能力(βp)和药物-蛋白复合物的解离常数(Kdp)。采用大鼠在体小肠回流实验装置,利用HPLC法同时测定十二指肠、空肠、回肠、结肠的肠循环液中间尼索地平消旋体及酚红的含量以计算4h药物吸收百分率,并探讨不同药物浓度、pH值和吐温80对肠吸收的影响。结果:0.2、0.5、1.0、2.0μg/ml尼索地平消旋体在大鼠血浆中的蛋白结合率分别为(96.38±3.6)%、(97.13±3.1)%、(97.27±2.8)%、(98.22±3.6)%,βp为4×10-4μmol/g,Kdp为7×10-4μmol/L。间尼索地平消旋体在十二指肠、空肠、回肠、结肠的4h吸收百分率分别为(51.26±1.09)%、(47.85±6.25)%、(43.63±1.986)%、(39.87±5.42)%,不同pH的肠循环液和不同浓度吐温80对其小肠吸收百分率无明显影响(P>0.05),其浓度与其小肠吸收百分率呈线性关系。结论:间尼索地平消旋体与大鼠血浆蛋白结合率很高,且呈浓度依赖性;其在全肠段吸收呈一级动力学方程,吸收机制为被动扩散。

OBJECTIVE：To study plasma protein binding rate and intestinal absorption kinetics of m-nisoldipine despinner in rats.METHODS：Equilibrium dialysis and HPLC were used to determine the protein binding rates of m-nisoldipine despinner（0.2,0.5,1.0,2.0μg/ml）in rat plasma.Apparent maximum capacity（βp）of drug binding by albumin and dissociation constant（Kdp）of drug-protein compound were calculated.In intestine reflux test,HPLC method was established for the content determination of m-nisoldipine despinner and phenolsulfonphthalein in the circulation solution of duodenum,jejunum,ileum and colon to calculate the percentage of drug absorption in 4 h,and the effects of different concentrations of drug,pH value and tween-80 on the absorption kinetics were investigated.RESULTS：The protein binding rates of m-nisoldipine despinner（0.2,0.5,1.0,2.0μg/ml）with rat plasma were（96.38±3.6）%,（97.13±3.1）%,（97.27±2.8）% and（98.22±3.6）%.βp was 4×10-4 μmol/g and Kdp was 7×10-4μmol/L.The percentages of drug absorption in 4 h were（51.26±1.09）%,（47.85±6.25）%,（43.63±1.986）% and（39.87±5.42）% in duodenum,jejunum,ileum and colon.Intestinal circulation solution with different pH value and different concentrations of tween-80 showed no significant effect on intestinal absorption percentage（P0.05）.A linear relation between the concentration of intestinal circulation solution and absorption percentage was found.CONCLUSIONS：The binding rates of m-nisoldipine despinner with rat plasma protein are in high level in concentration-dependant manner.The absorption of m-nisoldipine in rat＇s intestine is a first-order process with the passive diffusion mechanism.