Involvement of Influx and Efflux Transport Systems in Gastrointestinal Absorption of Celiprolol
Involvement of Influx and Efflux Transport Systems in Gastrointestinal Absorption of Celiprolol
复制标题
DOI：
10.1002/jps.21618
复制
发表时间：
2009-07-01
影响因子：
3.8
通讯作者：
Tsuji, Akira
中科院分区：
文献类型：
--
作者：
Kato, Yukio;Miyazaki, Tatsuya;Tsuji, Akira
柑橘汁可抑制几种β-受体阻滞剂的胃肠道吸收，但尚未确定其小肠吸收的分子机制。在这里，我们试图证明参与的流入和流出转运蛋白在体内胃肠道吸收塞利洛尔在小鼠。野生小鼠口服塞利洛尔（3 mg/kg）后血药浓度大多低于定量限，而mdr 1a/B基因敲除（mdr 1a/B（-/-））小鼠血药浓度明显高于野生小鼠，提示P-糖蛋白介导的外排。进一步考察塞利洛尔在mdr 1a/B（（-/-））小鼠体内的口服吸收情况，以探讨其内流转运机制，并避免P-糖蛋白的作用。同时给予溴磺酞（BSP），一种包括有机阴离子转运多肽（OATP）在内的多种内流转运蛋白的抑制剂，可降低血浆塞利洛尔浓度。在小肠组织的Ussing型腔室中证实了BSP对从顶端膜摄取塞利洛尔的抑制作用。在非洲爪蟾卵母细胞中也证实了人小肠转运蛋白OATP-A/1A 2对塞利洛尔的吸收。有趣的是，OATP-A/1A 2接受各种β-受体阻滞剂，包括醋丁洛尔、阿替洛尔和索他洛尔，其口服吸收可通过与柑橘汁或泰利霉素联合给药而抑制。综上所述，这些发现表明流入转运系统在塞利洛尔口服吸收中的基本作用。(C)2008 Wiley-Liss，Inc.和美国药学协会药物科学杂志98：2529-2539，2009
Gastrointestinal absorption of several beta-blockers is inhibited by citrus juices, although molecular mechanism(s) lying on their small intestinal absorption has not yet been identified. Here, we attempted to demonstrate involvement of both influx and efflux transporters in vivo in gastrointestinal absorption of celiprolol in mice. Plasma concentration of celiprolol (3 mg/kg) after oral administration was mostly under the limit of quantification in wild mice, whereas that in mdr1a/b knockout (mdr1a/b((-/-))) mice was much more obvious, indicating P-glycoprotein-mediated efflux. Then, the oral absorption of celiprolol in mdr1a/b((-/-)) mice was further examined to investigate influx transport mechanism with avoiding effect of P-glycoprotein. Coadministration of bromosulfophthalein (BSP), an inhibitor of various influx transporters including organic anion transporting polypeptide (OATP) reduced plasma celiprolol concentration. Inhibition by BSP of celiprolol uptake from apical membranes was confirmed in Ussing-type chamber of small intestinal tissues. Uptake of celiprolol by human small intestinal transporter OATP-A/1A2 was also confirmed in Xenopus Laevis oocytes. Interestingly, OATP-A/1A2 accepts various beta-blockers including acebutolol, atenolol and sotalol, oral absorption of which is inhibited by coadministration of citrus juice or telithromycin in human. Taken together, these findings have suggested fundamental role of influx transport system(s) in oral absorption of celiprolol. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2529-2539, 2009