OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine.
OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine.
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发表时间：
1999-08
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通讯作者：
M. Cvetkovic;B. Leake;M. Fromm;G. Wilkinson;R. Kim
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作者：
M. Cvetkovic;B. Leake;M. Fromm;G. Wilkinson;R. Kim
非索非那定是一种非镇静抗组胺药，不会发生显著的代谢生物转化。因此，假设摄取和外排转运体可能在药物的处置中起重要作用。利用重组痘苗病毒表达系统，发现有机阴离子转运多肽家族的成员，如人有机阴离子转运多肽(OATP)和大鼠有机阴离子转运多肽1和2(Oatp1和Oatp2)，介导了[(14)C]非非那定的细胞摄取。而胆汁酸转运蛋白人牛磺胆酸钠共转运蛋白多肽和大鼠有机阳离子转运蛋白rOCT1则无此活性。P-糖蛋白(P-gp)是一种非索非那定外排转运蛋白，使用缺乏P-gp的极化上皮细胞系LLCPK_1和高表达P-gp的衍生细胞系(L-mdr1)被鉴定为非索非那定外排转运体。此外，口服和静脉注射。给缺乏mdr1a编码P-gp的小鼠注射[(14)C]非索非那定，与野生型小鼠相比，血浆和大脑中的药物水平分别增加了5倍和9倍。此外，一些P-gp的药物抑制剂也被发现是OATP的有效抑制剂。由于OATP转运体和P-gp共同定位于肝脏等对药物处置具有重要作用的器官，它们的活性为迄今未知的导致非索非那定处置的机制(S)提供了解释，并提示在其他外源物质的处置中可能具有类似的作用。
Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.