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First published on May 5, 2005; DOI: 10.1124/jpet.105.085613

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Tsuneo Deguchi
Mizue Takemoto
Nao Uehara
W. Edward Lindup
Ayaka Suenaga
Masaki Otagiri
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Received for publication March 2, 2005.
Revised April 29, 2005.
Accepted for publication May 2, 2005.

Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

Tsuneo Deguchi 1, Mizue Takemoto 1, Nao Uehara 1, W. Edward Lindup 2, Ayaka Suenaga 1, Masaki Otagiri 1*

1 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 2 Department of Pharmacology and Therapeutics, University of Liverpool, L69 3BX, England

* Address correspondence to: E-mail: otagirim{at}gpo.kumamoto-u.ac.jp

Abstract

Hippurate (HA) is a harmful uremic toxin that accumulates during chronic renal failure and failure of the excretion system for uremic toxins is thought to be responsible. Recently, we reported that organic anion transporter 1 (rOat1) is the primary mediator of HA uptake in the kidney and so now we have studied the pharmacokinetics and tissue distribution of HA after a single i.v. dose of HA to normal and 5/6 nephrectomized rats (5/6Nx rats). In control rats, the renal and biliary clearances of HA were 18.1 and 0.1 mL/min/kg, respectively. Plasma clearance decreased as dosage increased from 0.1 to 5 mg/kg, which suggests that renal tubular secretion is the primary route for elimination of HA. The plasma clearance of HA was significantly decreased in 5/6 Nx rats, compared with normal rats. In 5/6 Nx rats, renal clearance of endogenous HA correlated more closely with clearance of p-aminohippurate (PAH) than with that of creatinine. Protein expression of rOat1 and rOat3, assessed by Western blot analysis, was decreased in 5/6 Nx rats. Furthermore, in 5/6 Nx rats, the renal secretory clearance of endogenous HA correlated closely with protein expression of renal rOats. Thus, HA is primarily eliminated from the plasma via the kidney by active tubular secretion. The renal clearance of endogenous HA appears to be a useful indicator of changes in renal secretion that accompany the reduced levels of OATs protein in chronic renal failure.


Key words: 5/6 nephrectomized rats, chronic renal failure, organic anion transporter, pharmacokinetics, renal tubular secretion, uremic toxin


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