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

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.