Emi Y, Tsunashima D, Ogawara K, Higaki K, Kimura T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
J Pharm Sci. 1998 Mar;87(3):295-9. doi: 10.1021/js970294v.
The intestinal transport of quinidine was characterized in rat small intestine, using the Ussing-type chamber under short-circuited conditions. In the short-circuited condition, quinidine transport was predominantly secretory and the transport rate in jejunum was 3.5 times larger in the secretory direction than that in the absorptive direction. The secretion of quinidine was found to be dependent upon its concentration and to be via a carrier-mediated system in both jejunum and ileum. Although the kinetic characteristic of the carrier-mediated secretion of quinidine was very similar in jejunum and ileum, its contribution was much greater in jejunum because of a higher passive diffusion component in ileum. The secretion of quinidine, well-known as an inhibitor of P-glycoprotein, was inhibited significantly and its absorption was enhanced significantly by several substrates of P-glycoprotein including verapamil, diltiazem, and digitoxin in jejunum. These phenomena were also observed by the addition of 2,4-dinitrophenol. Furthermore, the voltage-clamp studies indicated that the inhibition of quinidine secretion occurred in the transcellular pathway. On the other hand, neither tetraethylammonium nor p-aminohippuric acid affected the transport of quinidine. Quinidine was also recognized to inhibit the secretion and to promote the absorption of substrates of P-glycoprotein, chlorpromazine, and verapamil. These results strongly suggest that quinidine is not only an inhibitor but also a substrate of P-glycoprotein and that the P-glycoprotein-mediated secretory flux acts as a barrier to quinidine absorption in the small intestine, especially jejunum.
在短路条件下，使用Ussing型扩散盒对大鼠小肠中奎尼丁的肠道转运进行了表征。在短路条件下，奎尼丁的转运主要是分泌性的，空肠中分泌方向的转运速率比吸收方向的转运速率大3.5倍。发现奎尼丁的分泌取决于其浓度，并且在空肠和回肠中均通过载体介导的系统进行。尽管奎尼丁载体介导分泌的动力学特征在空肠和回肠中非常相似，但由于回肠中被动扩散成分较高，其在空肠中的作用更大。众所周知，奎尼丁是一种P-糖蛋白抑制剂，在空肠中，包括维拉帕米、地尔硫卓和洋地黄毒苷在内的几种P-糖蛋白底物可显著抑制其分泌，并显著增强其吸收。加入2,4-二硝基苯酚也观察到了这些现象。此外，电压钳研究表明，奎尼丁分泌的抑制发生在跨细胞途径中。另一方面，四乙铵和对氨基马尿酸均不影响奎尼丁的转运。奎尼丁还被认为可抑制P-糖蛋白底物、氯丙嗪和维拉帕米的分泌并促进其吸收。这些结果有力地表明，奎尼丁不仅是P-糖蛋白的抑制剂，也是其底物，并且P-糖蛋白介导的分泌通量在小肠尤其是空肠中对奎尼丁的吸收起到了屏障作用。
