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

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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.