MOLECULAR ANALYSIS OF CORRELATION BEIWEEN ALTERATIONS IN XENOBIOTIC TRANSPORTER EXPRESSIONS AND ATTENUATED DRUG EXCRETION IN RENAL FAILURE

肾衰竭中异生物转运蛋白表达的改变与药物排泄减弱之间相关性的分子分析

• 批准号: 12672152
• 负责人: SAITO Hideyuki
• 金额: $ 2.56万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672152/
• 关键词: DRUG TRANSPORTER; RENAL EXCRETION; ORGANIC IONS; RENAL FAILURE; PHARMACOKINETICS; GENE EXPRESSION; 賢排泄; 腎排泄

We investigated correlation between alterations in xenobiotic transporter expression in the kidney and attenuated drug excretion in rats with chronic renal failure. In the state of renal failure caused by 5/6 nephrectomy, the mRNA levels of OAT-K1 and OAT-K2, both kidney-specific organic anion transporters, were significantly diminished, and the renal clearance of methotrexate, a substrate of OAT-K1,2, was markedly decreased compared with that in sham-operated rats. The tubular secretion rates of both p-aminohippuric acid (PAH) and cemetidine wre markedly decreased in the 5/6 nephrectomized rats. The distribution rate of PAH into the kidney was unchaged, whereas the distribution rate of cimetidine into the kidney medulla was significantly decreased in the 5/6 nephrectomized rats. The expression level of the rOCT2 was markedly depressed in the rats with renal failure, but those of rOCT1m rOAT1 and rOAT3 were maintained. These findings could provide information for quantitative prediction and evaluation of pharmacokinetics based on the analysis of changes in expression levels of drug transporters in renal failure.

我们研究了慢性肾衰竭大鼠肾脏中异生物质转运蛋白表达的变化与药物排泄减弱之间的相关性。在5/6肾切除引起的肾衰竭状态下，肾脏特异性有机阴离子转运蛋白OAT-K1和OAT-K2的mRNA水平显着降低，并且OAT-K1的底物甲氨蝶呤的肾脏清除率显着降低。 ,2,与假手术大鼠相比显着降低。 5/6肾切除大鼠的肾小管对氨基马尿酸（PAH）和西咪替丁的分泌率均显着降低。在5/6肾切除大鼠中，PAH进入肾脏的分布率没有改变，而西咪替丁进入肾髓质的分布率显着降低。肾衰竭大鼠中rOCT2的表达水平显着降低，但rOCT1m、rOAT1和rOAT3的表达水平保持不变。这些发现可以为基于肾衰竭药物转运蛋白表达水平变化分析的药代动力学定量预测和评估提供信息。

项目成果

Okabe H: "Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction"J. Pharm. Pharmacol.. 54・1. 65-70 (2002)

Okabe H：“实验性肾功能障碍大鼠中他克莫司生物利用度增加的评估”J. Pharm. 54・1 (2002)。

齋藤 秀之: "薬物代謝からみた肝・腎・心疾患患者への医薬品投与時の注意"医薬ジャーナル社. 78 (2001)

齐藤英幸：“从药物代谢的角度看肝、肾、心脏病患者用药时的注意事项” Iyaku Journal Inc. 78 (2001)

Urakami Y: "Hormonal regulation of organic cation transporter OCT2 expression in rat kidney"FEBS Lett.. 473・2. 173-176 (2000)

浦上Y：“大鼠肾脏中有机阳离子转运蛋白OCT2表达的激素调节”FEBS Lett.. 473・2（2000）。

Terada T: "Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2"Pflugers Arch.. 440・5. 261-265 (2000)

Terada T：“确定肽转运蛋白 PEPT1 和 PEPT2 的底物亲和力的结构要求”Pflugers Arch.. 440・5 (2000)。

Inui K: "Physiological and pharmacological implications of peptide transpsorters, PEPT1 and PEPT2"Nephrol.Dial.Transplant.. 15・suppl6. 11-13 (2000)

Inui K：“肽转运蛋白、PEPT1 和 PEPT2 的生理学和药理学意义” Nephrol.Dial.Transplant.. 15·suppl6 (2000)。