Regulation Mechanisms of Drug Disposition via H^+-Coupled Active Transport Systems in the Intestinal and Renal Tubular Epithelial Cells

吸收和分泌过程对药物在体内的处置起着重要的调节作用。利用分离的质膜囊泡，我们在肾刷状缘膜上显示了H~+/有机阳离子逆向转运系统(分泌)，在肠刷状缘膜上显示了H~+/氨基-β-内酰胺类抗生素(二肽)共转运系统(吸收)。在本研究中，我们研究了H~+偶联转运系统的结构和调控机制。与有机阴离子和D-葡萄糖转运系统相比，肾刷状缘膜H~+/有机阳离子逆向转运系统对pH非常敏感(最适pH为7.0)，pH是调节H~(++)/有机阳离子逆向转运系统活性的重要因素，以及H~(2+)梯度(驱动力)。具有α-氨基和羧基的头孢拉定等氨基头孢菌素通过H~(2+)/二肽共转运系统在肠道刷状缘膜上转运。头孢克昔姆，一种新的P.O.具有两个羧基的头孢菌素只在酸性pH区通过二肽载体以向内的H~+梯度转运，而头孢拉定在中性和酸性pH区都通过二肽载体转运，这表明二肽类物质存在多种转运系统。采用化学修饰技术，考察了巯基、组氨酸、酪氨酸和羧基对H~+/有机阳离子对位体系和H~+/二肽共转运体系的影响。组氨酸是两种转运系统所必需的，而巯基是H~+/有机阳离子反转运系统所必需的。

The absorptive and the secretory processes play important roles for the regulation of drug disposition in the body. Using the isolated plasma membrane vesicles, we have demonstrated H^+/organic cation antiport system (secretion) in renal brush border membranes and H^+/amino-beta-lactam antibiotic (dipeptide) cotransport system (absorption) in the intestinal brush border membranes. In the present study, we examined the structure and the regulatory mechanisms for H^+ coupled transport systems.1. The H^+/organic cation antiport system in renal brush border membranes is very sensitive to pH (optimum pH of 7.0), in contrast to organic anion and D-glucose transport systems, and that pH is an important factor to regulate the activity of the H^+/organic cation antiport system, as well as H^+ gradient (a driving force).2. Aminocephalosporins, such as cephradine, possessing an alpha-amino group and a carboxyl group, were transported via H^+/dipeptide cotransport system in the intestinal brush border membranes. Cefixime, a new p.o. cephalosporin with two carboxyl groups, was transported by an inward H^+ gradient via dipeptide carrier only in an acidic pH region, whereas cephradine is transported via dipeptide carrier in both neutral and acidic pH regions, suggesting the existence of multiple transport systems for dipeptides.3. Using the chemical modification technique to the membranes, we examined the role of sulfhydryl, histidine, tyrosine and carboxyl groups on the H^+/organic cation antiport system and H^+/dipeptide cotransport system. Histidine group was essential for both transport systems, and sulfhydryl group was essential for the H^+/organic cation antiport system.