布洛芬葡萄糖醛酸结合物的立体选择性胆排泄及其机制研究

摘要/Abstract

摘要： 目的: 为阐明药物转运体在布洛芬(IB)葡萄糖醛酸结合物(IBG)胆排泄中的作用, 对IB 和IBG在先天性高胆红素血症大鼠(EHBR)和正常SD 大鼠(SDR)的胆排泄和血药浓度差异进行了研究。方法: 按20 mg/kg 剂量静脉注射IB 消旋体后, 以HPLC法测定了血和胆汁中IB 与IBG 的浓度。结果: 结果表明IBG 的胆排泄在EHBR 受到了明显抑制, 其S-型和R-型IBG 的6 小时胆排泄量分别为给药量的1. 7 %±1. 0 % 和0. 6 % ±0. 9 %, 而在SDR, 该值分别为18. 4 %±4. 0 % 和3. 0 %±2. 4 %。这些结果同时显示了S-型IBG 在两种大鼠的胆排泄量均较R-型IBG大, 说明该过程存在明显的立体选择性。由于IBG 在EHBR 的胆排泄受到抑制, 其血中的浓度较高。结论: EHBR 是一种先天性多药耐药相关蛋白(Mrp2)缺失的大鼠, 可以推测布洛芬葡萄糖醛酸结合物的胆排泄过程主要是由Mrp2 介导。但由于IBG 在EHBR 仍有少量胆排泄, 故不排除其它转运体参与该过程的可能性。

关键词: 布洛芬, 葡萄糖醛酸结合物, EHBR, Mrp2, 胆排泄, 立体选择性

Abstract: AIM: To illustrate the effects of drug transporters on the bile efflux of ibuprofen glucuronide (IBG), the difference of bile excretion and plasma concentration of ibuprofen(IB)and its glucuronides was studied in EHBR and normal SD rat(SDR).METHODS: After 20 mg/kg of IB enantiomers administrated intravenously, the bile and blood were collected from the rats and the concentration of IB and their glucuronide were measured by HPLC methods.RESULTS: The bile excretion of IBG was obviously (but no totally)suppressed in EHBR (1.7 %±1.0 %, 0.6 %±0.9 % of the dose respectively for S-IBG and R-IBG)compared with that in SDR (18.4 %±4.0 %and 3.0 %±2.4 % of the dose respectively for S-IBG and R-IBG), for both kinds of rats, there are more S-IBG excreted than that of R-IBG.As the result of reduction of IBG excreted in bile, the concentration of IBG was higher in blood in EHBRs.CONCLUSION: The results suggest that Mrp2 is the most important transporter for IBG, and other transporter(s)may participate in the process.

Key words: ibuprofen, glucuronide, EHBR, Mrp2, bile excretion, stereoselectivity

. 布洛芬葡萄糖醛酸结合物的立体选择性胆排泄及其机制研究[J]. 中国临床药理学与治疗学, 2007, 12(10): 1163-1167.

CHEN Xi-jing, Masahiro Iwaki. Stereoselective bile excretion of ibuprofen glucuronide and the transport mechanism in the biliary efflux[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(10): 1163-1167.

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