Evaluation of drug interaction and interindividual differences of renal drug excretion based on the genetic polymorphism analysis

基于遗传多态性分析评价药物相互作用及肾脏药物排泄个体差异

• 批准号: 13307068
• 负责人: INUI Ken-ichi
• 金额: $ 30.95万
• 依托单位: KYOTO UNIVERSTTY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307068/
• 关键词: Drug transporter; Personalized pharmacotherapy; Interindividual differences; Genetic polymorphism; Expression profile; Detoxification system; Renal excretion; Organic ion; 尿細管分泌; オーダーメイド薬物療法; アニオン性薬物; カチオン性薬物; ペプチド類似薬物; 有機カチオン; 有機アニオン; 腎疾患

Drug transporters expressed in the kidney play important roles for elimination of number of hydrophilic compounds such as drugs, toxins and endogenous compounds. In the present study, we evaluated interindividual differences of pharmacokinetic (PK) properties based on the genetic information and expression profiles of human renal drug transporters.We have identified and characterized novel renal specific transporters hOCT2-A and NaGLT1. Expression profiles for various drug transporters such as organic ion transporters in the human kidney were constructed. We have identified single nucleotide polymorphisms for coding region (cSNPs) of hOCT1 and hPEPT2 with decreasing the functional activities, but the appearance rates of these SNPs were very low. The correlation analyses between expression of drug transporters and PK properties in renal failure patients and model animals indicated that expression levels of renal drug transporters are responsible for interindividual differences of drug renal excretion. These findings could provide information for quantitative prediction and evaluation of PK based on the expression levels of renal drug transporters.

肾脏中表达的药物转运蛋白对于消除多种亲水性化合物（例如药物、毒素和内源性化合物）发挥着重要作用。在本研究中，我们根据人肾药物转运蛋白的遗传信息和表达谱评估了药代动力学（PK）特性的个体差异。我们已经鉴定并表征了新型肾脏特异性转运蛋白 hOCT2-A 和 NaGLT1。构建了各种药物转运蛋白（例如人肾中有机离子转运蛋白）的表达谱。我们已经鉴定出hOCT1和hPEPT2的编码区（cSNP）的单核苷酸多态性会降低功能活性，但这些SNP的出现率非常低。肾衰竭患者和模型动物中药物转运蛋白的表达与PK特性的相关性分析表明，肾脏药物转运蛋白的表达水平是药物肾排泄个体间差异的原因。这些发现可以为基于肾脏药物转运蛋白表达水平的PK定量预测和评估提供信息。

项目成果

Ohnishi et al.: "Distinct transport activity of tetraethylammonium from L-carnitine in rat renal brush-border membranes"Biochim.Biophys.Acta. 1609・2. 218-224 (2003)

Ohnishi 等：“大鼠肾刷状缘膜中左旋肉碱的四乙铵的独特转运活性”Biochim.Biophys.Acta 1609·2（2003）。

Goto et al.: "C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation"Pharmacogenetics. 12・6. 451-457 (2002)

Goto 等：“MDR1 基因中的 C3435T 多态性影响活体肝移植受者中 CYP3A4 的肠上皮细胞表达水平，而不是 Pgp”药物遗传学 12・6 (2002)。

Urakami et al.: "cDNA cloning functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney."J.Am.Soc.Nephrol.. 13(7). 1703-1710 (2002)

Urakami 等人：“主要在人肾中表达的有机阳离子转运蛋白 hOCT2 的选择性剪接变体的 cDNA 克隆功能表征和组织分布。”J.Am.Soc.Nephrol.. 13(7)。

Takahashi et al.: "Upregulation of H^+-peptide cotransporter PEPT2 in rat remnant kidney"Am.J.Physiol.Renal Physiol.. 281(6). F1109-F1116 (2001)

Takahashi等人：“大鼠残肾中H 2 -肽协同转运蛋白PEPT2的上调”Am.J.Physiol.Renal Physiol..281(6)。

Terada et al.: "Genetic variant Arg57His in human H+/peptide cotransporter 2 causes a complete loss of transport function"Biochem. Biophys.Res.Common.. 316(2). 416-420 (2004)

Terada 等人：“人 H/肽协同转运蛋白 2 中的基因变异 Arg57His 导致转运功能完全丧失”Biochem。