Uptake/Efflux Transport of Tramadol Enantiomers and O-Desmethyl-Tramadol: Focus on P-Glycoprotein
Uptake/Efflux Transport of Tramadol Enantiomers and O-Desmethyl-Tramadol: Focus on P-Glycoprotein
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DOI：
10.1111/j.1742-7843.2009.00428.x
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发表时间：
2009-09-01
影响因子：
3.1
通讯作者：
Desmeules, Jules
中科院分区：
文献类型：
--
作者：
Kanaan, Mouna;Daali, Youssef;Desmeules, Jules
曲马多(TMD)的镇痛作用源于其两个对映体(+)-TMD和(-)-TMD及其阿片代谢物(+)-O-去甲基曲马多(M1)的单胺能效应。P-糖蛋白(P-gp)可能在TMD的止痛和耐受性变化中起重要作用。本研究利用Caco-2细胞单层模型研究了P-gp在(+)-TMD、(-)-TMD和M1跨上皮转运中的作用。在两种pH条件(pH 6.8/7.4和7.4/7.4)下，研究了外消旋TMD和M1(1-100 mU M)在P-gp抑制剂环孢素A(10 MU M)存在和不存在的情况下的双向转运，并用更有效和特异的P-gp抑制剂GF120918(4 MU M)进行了评估。用与荧光检测器联用的高效液相色谱进行分析定量。当施加pH梯度时，观察到(+)-TMD、(-)-TMD和M1的净分泌(TR：P-APP(B-A)/P-APP(A-B)：1.8-2.7；P<；0.05)。然而，在非梯度体系中，所有化合物的双向传输是相等的。在P-gp抑制剂存在的情况下，在两种pH条件下，分泌通量都有轻微但显著的增加(高达26%；P<；0.05)。结论：(+)-TMD、(-)-TMD和M1不是P-gp底物。然而，基于质子的外排泵可能参与限制TMD对映体的胃肠道吸收，以及增加TMD对映体和M1肾脏排泄。提示摄取载体可能参与TMD对映体和M1的跨上皮转运。
The analgesic effect of tramadol (TMD) results from the monoaminergic effect of its two enantiomers, (+)-TMD and (-)-TMD as well as its opioid metabolite (+)-O-desmethyl-tramadol (M1). P-glycoprotein (P-gp) might be of importance in the analgesic and tolerability profile variability of TMD. Our study investigated the involvement of P-gp in the transepithelial transport of (+)-TMD, (-)-TMD and M1, using a Caco-2 cell monolayer model. The bidirectional transport of racemic TMD and M1 (1-100 mu M) across the monolayers was investigated at two pH conditions (pH 6.8/7.4 and 7.4/7.4) in the presence and absence of P-gp inhibitor cyclosporine A (10 mu M) and assessed with the more potent and specific P-gp inhibitor GF120918 (4 mu M). Analytical quantification was performed by liquid chromatography coupled to the fluorescence detector. A net secretion of (+)-TMD, (-)-TMD and M1 was observed when a pH gradient was applied (TR: P-app(B - A)/P-app(A - B): 1.8-2.7; P < 0.05). However, the bidirectional transport of all compounds was equal in the non-gradient system. In the presence of P-gp inhibitors, a slight but significant increase of secretory flux was observed (up to 26%; P < 0.05) at both pH conditions. In conclusion, (+)-TMD, (-)-TMD and M1 are not P-gp substrates. However, proton-based efflux pumps may be involved in limiting the gastrointestinal absorption of TMD enantiomers as well as enhancing TMD enantiomers and M1 renal excretion. A possible involvement of uptake carriers in the transepithelial transport of TMD enantiomers and M1 is suggested.