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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571092/
• 关键词: Intestinal Epithelial Cell; Renal Tubular Epithelial Cell; Brush Border Membrane; Absorption and Secretion; Active Transport; Organic Cation; beta-Lactam Antibiotic; H^+-Coupled Transport; 有機アニオン; 吸収分泌; βーラクタム抗生物質

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.

吸收和分泌过程对药物在体内的分布起着重要的调节作用。利用分离的质膜囊泡，我们证明了肾刷状缘膜中的H^+/有机阳离子逆向转运系统（分泌）和肠刷状缘膜中的H^+/氨基-β-内酰胺抗生素（二肽）共转运系统（吸收）。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。与有机阴离子和D-葡萄糖转运系统相比，肾刷状缘膜上的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，H^+梯度也是一种驱动力.氨基头孢菌素，如头孢拉定，具有α-氨基和羧基，通过H^+/二肽共转运系统在肠刷状缘膜中转运。头孢克肟，一种新的口服药。具有两个羧基的头孢菌素仅在酸性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区均通过二肽载体转运，提示二肽存在多个转运系统.利用化学修饰技术，研究了巯基、组氨酸、酪氨酸和羧基在H^+/有机阳离子反向转运系统和H^+/二肽共转运系统中的作用。组氨酸基团对这两种转运系统都是必需的，巯基对H^+/有机阳离子逆向转运系统是必需的。

项目成果

M. Takano, T. Okano, K. Inui, and R. Hori: "Transport of cephalosporin antibiotics in rat renal basolateral membranes." J. Pharm. Pharmacol.41. 795-796 (1989)

M. Takano、T. Okano、K. Inui 和 R. Hori：“头孢菌素抗生素在大鼠肾基底外侧膜中的转运。”

M. Kato, H. Maegawa, T. Okano, K. Inui, and R. Hori: "Effect of various chemical modifiers on H^+ coupled transport of cephradine via dipeptide carriers in rabbit intestinal brush-border membranes: Role of histidine residues." J. Pharmacol. Exp. Ther. 251

M. Kato、H. Maekawa、T. Okano、K. Inui 和 R. Hori：“各种化学修饰剂对兔肠刷状缘膜中头孢拉定通过二肽载体的 H^ 偶联转运的影响：组氨酸残基的作用。

乾賢一: 薬学雑誌. 108. 921-937 (1988)

Kenichi Inui：制药杂志 108. 921-937 (1988)

H.Maegawa: J.Biol.Chem.263. 11150-11154 (1988)

H.前川：J.Biol.Chem.263。

M.Kato: "Effect of various chemical modifiers on H^+coupled transport of cephradine via dipeptide carriers in rabbit intestinal brush-border membranes:Role of histidine residues." J.Pharmacol.Exp.Ther. 251. 745-749 (1989)

M.Kato：“各种化学修饰剂对兔肠刷状缘膜中头孢拉定通过二肽载体的 H^ 偶联转运的影响：组氨酸残基的作用。”