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

肠和肾小管上皮细胞中H^耦合主动转运系统的药物处置调节机制

基本信息

批准号：
63571092
负责人：
INUI Ken-ichi
金额：
$ 1.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

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.

吸收和分泌过程对于体内药物分布的调节起着重要作用。使用分离的质膜囊泡，我们证明了肾刷状缘膜中的H^+/有机阳离子反转运系统（分泌）和肠刷状缘中的H^+/氨基-β-内酰胺抗生素（二肽）共转运系统（吸收）膜。在本研究中，我们研究了H^+耦合运输系统的结构和调控机制。1．与有机阴离子和D-葡萄糖转运系统相比，肾刷状缘膜中的H^+/有机阳离子反向转运系统对pH非常敏感（最适pH为7.0），并且pH是调节肾刷状缘膜中H^+/有机阳离子反向转运系统活性的重要因素。 H^+/有机阳离子反港系统，以及H^+梯度（驱动力）。2．氨基头孢菌素，例如头孢拉定，具有α-氨基和羧基，通过肠刷状缘膜中的H^+/二肽共转运系统转运。头孢克肟，一种新的邮政信箱具有两个羧基的头孢菌素仅在酸性 pH 区域通过二肽载体通过向内 H^+ 梯度转运，而头孢拉定在中性和酸性 pH 区域均通过二肽载体转运，表明二肽存在多种转运系统。 3.利用膜的化学修饰技术，我们研究了巯基、组氨酸、酪氨酸和羧基对H^+/有机阳离子反向转运系统和H^+/二肽共转运系统的作用。组氨酸基团对于两种转运系统都是必需的，而巯基对于H^+/有机阳离子反向转运系统是必需的。