Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
J Pharm Pharmacol. 1996 Oct;48(10):1083-9. doi: 10.1111/j.2042-7158.1996.tb05904.x.
Because the significance of P-glycoprotein in the in-vivo secretion of beta-blockers in intestinal epithelial cells is unclear, the secretory mechanism for beta-blockers and other drugs has been evaluated. Uptake of the beta-blockers acebutolol, celiprolol, nadolol and timolol, and the antiarrhythmic agent, quinidine by the multidrug-resistant leukaemic cell line variant K562/ADM was significantly lower than that by drug-sensitive K562 cells, suggesting that these beta-blockers are transported by P-glycoprotein out of cells. The reduced uptake of acebutolol by the drug-resistant K562/ADM cells was reversed by treating the cells with anti-P-glycoprotein monoclonal antibody, MRK16, whereas no such alteration in uptake was observed for drug-sensitive K562 cells. Acebutolol uptake by K562/ADM cells was, moreover, markedly enhanced, in a concentration-dependent manner, in the presence of the specific P-glycoprotein inhibitors, MS-209 and cyclosporin. Caco-2 cells were used for evaluation of the role of P-glycoprotein in intestinal permeability to drugs in-vitro. Basolateral-to-apical transport of acebutolol was twice that in the reverse direction. A similar polarized flux was also observed in the transport of vinblastine, but not in that of acetamide or mannitol. When in-vivo intestinal absorption was evaluated by the rat jejunal loop method, with simultaneous intravenous administration of a P-glycoprotein inhibitor, cyclosporin, intestinal absorption of both acebutolol and vinblastine increased 2.6- and 2.2-fold, respectively, but no such enhancement was observed in the absorption of acetamide. The effect of cyclosporin on the intestinal absorption of several drugs was further examined, and the extent of the contribution of P-glycoprotein as an absorption barrier to those drugs was evaluated. ATP depletion by occlusion of the superior mesenteric artery resulted in a clear increase in epithelial permeability to vinblastine, but not to 3-O-methylglucose or acetamide, indicating that vinblastine is secreted by ATP-dependent P-glycoprotein into the lumen. These findings demonstrate that P-glycoprotein plays a role as an absorption barrier by transporting several drugs from intestinal cells into the lumen.
由于P-糖蛋白在肠道上皮细胞中对β受体阻滞剂体内分泌的意义尚不清楚，因此对β受体阻滞剂及其他药物的分泌机制进行了评估。多药耐药白血病细胞系变体K562/ADM对β受体阻滞剂醋丁洛尔、塞利洛尔、纳多洛尔和噻吗洛尔以及抗心律失常药奎尼丁的摄取显著低于药物敏感的K562细胞，这表明这些β受体阻滞剂是通过P-糖蛋白转运出细胞的。用抗P-糖蛋白单克隆抗体MRK16处理耐药的K562/ADM细胞后，醋丁洛尔摄取减少的情况得到逆转，而药物敏感的K562细胞未观察到摄取有此类改变。此外，在特异性P-糖蛋白抑制剂MS-209和环孢素存在的情况下，K562/ADM细胞对醋丁洛尔的摄取以浓度依赖的方式显著增强。Caco-2细胞用于体外评估P-糖蛋白在药物肠道通透性中的作用。醋丁洛尔从基底侧向顶端的转运是反向转运的两倍。在长春碱的转运中也观察到类似的极化通量，但在乙酰胺或甘露醇的转运中未观察到。当通过大鼠空肠袢法评估体内肠道吸收，并同时静脉注射P-糖蛋白抑制剂环孢素时，醋丁洛尔和长春碱的肠道吸收分别增加了2.6倍和2.2倍，但乙酰胺的吸收未观察到此类增强。进一步研究了环孢素对几种药物肠道吸收的影响，并评估了P-糖蛋白作为这些药物吸收屏障的贡献程度。通过阻断肠系膜上动脉导致ATP耗竭，使上皮细胞对长春碱的通透性明显增加，但对3-O-甲基葡萄糖或乙酰胺的通透性未增加，这表明长春碱是由ATP依赖的P-糖蛋白分泌到肠腔中的。这些发现表明，P-糖蛋白通过将几种药物从肠道细胞转运到肠腔中而起到吸收屏障的作用。
