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.

我们研究了慢性肾功能衰竭大鼠肾脏异物转运体表达的变化与药物排泄减少之间的相关性。在5/6肾切除所致的肾功能衰竭状态下，肾组织特异性有机阴离子转运体OAT-K1和OAT-K2的mRNA水平显著降低，OAT-K1、2的底物甲氨蝶呤的肾清除量显著降低。在5/6肾切除大鼠，对氨基马酸(PAH)和西咪替丁的肾小管分泌率均显著降低。在5/6肾切除大鼠中，多环芳烃在肾脏中的分配率没有改变，而西咪替丁在肾髓质中的分配率显著降低。肾功能衰竭大鼠rOCT2的表达水平明显降低，而rOCT1M、rOAT1和rOAT3的表达水平保持不变。这些发现可以为基于肾功能衰竭时药物转运体表达水平变化的药代动力学定量预测和评估提供信息。

项目成果

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Yamaguchi H：“人肠细胞系 Caco-2 中格帕沙星和左氧氟沙星的转运特性”Eur. J. Pharmacol.. 431・3 (2001)。

乾 賢一: "生物薬剤学"南江堂. 284 (2001)

Kenichi Inui：“生物制药” Nankodo 284 (2001)。

Urakami Y: "Distinct characteristecs of organic cation transporters, OCT1 an OCT2, in the basolateral membrane of renal tubules"Pharm. Res.. 18・11. 1528-1534 (2001)

浦上Y：“肾小管基底外侧膜中有机阳离子转运蛋白OCT1和OCT2的独特特征”Res.18・11（2001）。

齋藤秀之: "月刊薬事臨時増刊号:医薬品適正使用のための臨床薬物動態"じほう. 834 (2000)

Hideyuki Saito：“每月药事特刊：正确使用药物的临床药代动力学”Jiho 834 (2000)。

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)