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 rat 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 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 seems to be a useful indicator of changes in renal secretion that accompany the reduced levels of OAT protein in chronic renal failure.
Footnotes
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This work was supported, in part, by the Sasakawa Scientific Research Grant from The Japan Science Society.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.085613.
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ABBREVIATIONS: CRF, chronic renal failure; HA, hippurate; 5/6 Nx rats, 5/6 nephrectomized rats; rOat, rat organic anion transporter; OAT, organic anion transporter; PAH, p-aminohippuric acid; BUN, blood urea nitrogen; HPLC, high-performance liquid chromatography; GFR, glomerular filtration rate; TBS-T, Tris-buffered saline/Tween 20; OCT, organic cation transporter; hOAT1, human organic anion transporter 1.
- Received March 1, 2005.
- Accepted May 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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