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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 16, 2005; DOI: 10.1124/jpet.105.094052

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Received for publication August 10, 2005.
Revised November 11, 2005.
Accepted for publication November 14, 2005.

Is the monkey an appropriate animal model to examine drug-drug interactions involving renal clearance? Effect of probenecid on the renal elimination of H2 receptor antagonists

Harunobu Tahara 1, Hiroyuki Kusuhara 1, Michihiro Chida 2, Eiichi Fuse 2, Yuichi Sugiyama 1*

1 The University of Tokyo 2 Kyowa Hakko Kogyo Co., Ltd

* Address correspondence to: E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

Abstract

The renal drug-drug interaction between famotidine (an H2 receptor antagonist) and probenecid has not been reproduced in rats. We have proposed that this is due to 1) a species difference in the transport activity by h/rOAT3, and 2) the expression of OCT1 in the rodent kidney (Tahara et al. J Pharmacol Exp Ther, 315:1-9, 2005). Since monkey OATs (mkOATs) exhibit similar transport activities to human orthologs, it is hypothesized that in vivo studies in monkeys will allow a more precise prediction of renal drug-drug interactions in humans. Famotidine and cimetidine were efficiently taken up by mkOAT3-expressing HEK cells (Km 154 and 71 µM, respectively), and their uptake was strongly inhibited by probenecid (Ki 3.0-5.7 µM). Quantification of mkOCT1 and mkOCT2 mRNAs in the monkey kidney using real- time RT-PCR revealed their predominant expression in the liver and kidney, respectively. Crossover studies were conducted in cynomolgus monkeys. Famotidine was given by intravenous administration, with or without probenecid. Probenecid-treatment caused a 65% reduction in the renal clearance (0.426±0.079 versus 0.165& [plusmn]0.027 L/h/kg), and a 90% reduction in the tubular secretion clearance (0.275±0.075 versus 0.0230±0.0217 L/h/kg), while it had no effect on the renal clearance of cimetidine. In contrast to the species-dependent effect of probenecid, allometric scaling using animal data (rat, dog and monkey) successfully predicted the renal and tubular secretion clearance of famotidine in humans. These results suggest that monkeys are more appropriate animal species for predicting the renal drug-drug interactions in humans.


Key words: H2-receptor antagonists, OAT, cynomolgus monkey, drug-drug interaction, organic anion transporter, tubular secretion


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