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First published on January 7, 2008; DOI: 10.1124/dmd.107.019869

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Received for publication November 26, 2007.
Revised December 30, 2007.
Accepted for publication January 2, 2008.

Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2) and rMATE1 (Slc47a1) in ischemia/reperfusion-induced acute kidney injury

Takanobu Matsuzaki 1, Takafumi Morisaki 1, Wakako Sugimoto 1, Koji Yokoo 1, Daisuke Sato 1, Hiroshi Nonoguchi 2, Kimio Tomita 2, Tomohiro Terada 3, Ken-ichi Inui 3, Akinobu Hamada 1, Hideyuki Saito 1*

1 Department of Pharmacy, Kumamoto University Hospital 2 Department of Nephrology, Kumamoto University Graduate School of Medical Sciences 3 Department of Pharmacy, Kyoto University Hospital

* Address correspondence to: E-mail: saitohide{at}fc.kuh.kumamoto-u.ac.jp

Abstract

In the proximal tubules of rat kidney, the polyspecific organic cation transporters, rOCT1 and rOCT2, mediate the basolateral uptake of various organic cations, including many drugs, toxins, and endogenous compounds, and the apical type of H+/organic cation antiporters, rat multidrug and toxin extrusion 1, rMATE1, mediate the efflux of organic cations. Renal clearances of H2-receptor antagonists, including famotidine, were reported to be decreased in patients kidney disease. Therefore, acute kidney injury (AKI) could influence renal excretion and disposition of organic cations accompanied by the regulation of organic cation transporters. The aim of this study was to investigate the pharmacokinetic alteration of cationic drugs and the expression of tubular organic cation transporters, rOCT1, rOCT2 and rMATE1, in ischemia/reperfusion (I/R)-induced AKI rats. I/R-induced AKI increased the plasma concentration of intravenously administrated famotidine, a substrate for rOCT1 and rOCT2, or tetraethylammonium (TEA), a substrate for rOCT1, rOCT2 and rMATE1. The area under the plasma concentration curve (AUC) for famotidine and TEA was 2-fold and 6-fold higher in I/R rats than in sham-operated rats, respectively. The accumulation of TEA into renal slices was significantly decreased, suggesting that organic cation transport activity at the basolateral membranes was reduced in I/R rat kidney. The protein expressions of basolateral rOCT2 and luminal rMATE1 were down-regulated in I/R rat kidneys. These data suggest that the urinary secretion of cationic drugs via epithelial organic cation transporters is decreased in AKI.


Key words: drug transport, ischemia/reperfusion injury, organic cation transport, pharmacokinetics, renal disposition, renal transport




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