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

在肾脏中表达的药物转运体在消除药物、毒素和内源性化合物等许多亲水性化合物方面起着重要作用。在本研究中，我们基于人类肾脏药物转运体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。我们已经鉴定并鉴定了新的肾特异性转运蛋白hOCT2-A和NaGLT1。构建了多种药物转运体（如有机离子转运体）在人体肾脏中的表达谱。我们发现了hOCT1和hPEPT2编码区的单核苷酸多态性（csnp），其功能活性降低，但这些snp的出现率很低。肾功能衰竭患者和模型动物体内药物转运蛋白表达与PK特性的相关性分析表明，肾脏药物转运蛋白的表达水平与药物肾排泄的个体差异有关。这些发现可为基于肾脏药物转运体表达水平的定量预测和评价PK提供信息。

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.