外翻肠囊法研究奥硝唑对映体在大鼠不同肠段的吸收特性

摘要

目的：考察奥硝唑在大鼠各肠段的吸收特性及奥硝唑两手性对映体在大鼠不同肠段吸收的差异性。方法采用大鼠外翻肠囊法，以HPLC手性色谱柱法测定奥硝唑在不同肠段的吸收量以及S‐奥硝唑及R‐奥硝唑的同一肠段肠吸收量，并分别计算吸收速率常数（Ka ）和表观渗透系数（Papp ），同法考察了P‐蛋白抑制剂（维拉帕米和环孢素A）对奥硝唑肠吸收特性的影响。结果奥硝唑在不同肠段吸收均呈线性，符合零级药物吸收速率，吸收趋势为空肠＞回肠＞结肠。在空肠段两对映体以近于1∶1的比例同时吸收，吸收速率不存在显著差异，随着供试液中奥硝唑质量浓度的上升，Ka呈线性增加（R2＞0．99），Paap基本保持不变，P‐蛋白抑制剂对奥硝唑的肠吸收没有显著性影响（P＞0．05）。结论奥硝唑在不同肠段的吸收有差异，空肠部位是吸收的最佳部位（P＜0．05），S‐奥硝唑与R‐奥硝唑在肠道中吸收速率不存在显著差异，吸收以被动扩散机制为主，奥硝唑不是 P‐糖蛋白的底物。%Objective To study the absorption characteristics of ornidazole and the absorption difference of ornidazole enantiomers at different intestine segments by isolated in vitro‐everted sac intestine model ,and to investigate the effect of P‐inhibitors to ornidazole intestinal absorption .Methods Rat in vitro‐everted intestine sac was used to determine the characteristics of ornidazole . The concentration of ornidazole and its enantiomers at different intestine segments were determined by HPLC equipped with chiral chromatographic column .Then the constant of absorption rate(Ka ) and the apparent permeability coefficient (Papp ) were calculat‐ed .Same method was applied in investigating the impact of the P‐glycoprotein inhibitors(verapamil and cyclosporin A) on the ab‐sorption of ornidazole in intestinal segments .Results The absorption of ornidazole in different intestinal segments showed a linear absorption and complied with the zero order kinetics .The descending order of ornidazole absorption was jejunum ,ileum and colon . There was no significant difference among the absorption rate of the two enantiomers .Ka increased linearly (R2 >0 .99) and Paap re‐mained unchanged with the rise of concentration for ornidazole in solution at jejunum .P‐protein inhibitors had no significant effect on the intestinal absorption(P>0 .05) .Conclusion The absorption of ornidazole in different intestinal segments was different and the Ka and Paap at jejunum were significantly higher than that at the other segments of intestine (P<0 .05) .There was no signifi‐cant difference between S‐ornidazole and R‐ornidazole in the intestinal absorption rate and met the passive transport mechanism . Ornidazole would not be the substrate of P‐protein inhibitor .