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Research ArticleArticle

Differences in Excretion of Hippurate, as a Metabolite of Benzoate and as an Administered Species, in the Single-Pass Isolated Perfused Rat Kidney Explained

Wanping Geng and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 597-606;
Wanping Geng
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K. Sandy Pang
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This article has a correction. Please see:

  • Correction for vol. 288, p. 597 - June 01, 1999

Abstract

The extents of excretion of [14C]hippurate and [3H]hippurate were compared in the single-pass, constant flow (8 ml/min) isolated rat kidney which was perfused simultaneously with tracer concentrations of [14C]benzoate and [3H]hippurate. The steady-state renal extraction ratio of [14C]benzoate was 0.26 ± 0.04 and was associated with a renal clearance of 1.13 ± 0.17 ml/min/g. The urinary clearance of [14C]benzoic acid was low (0.011 ± 0.01 ml/min/g), yielding a low fractional excretion [unbound urinary clearance/glomerular filtration rate (GFR)] value of 0.27 ± 0.19 and suggesting that glycination of [14C]benzoate to [14C]hippurate accounted almost completely for the total renal clearance. Fractional excretion for preformed [3H]hippurate was eight times that of GFR, but the steady-state renal extraction ratio of preformed [3H]hippurate, E{pmi} (0.24 ± 0.05) was much lower than the apparent extraction ratio of the renally formed [14C]hippuric acid [E{mi} = 0.39 ± 0.09] (p < .05). The theoretical basis for the discrepancy was explored with mathematical formulations developed from a physiologically based model of the kidney. It was found that parent drug kinetic parameters (transport and metabolic intrinsic clearance of benzoate) were unimportant for E{mi} or E{pmi}. Rather, the value of EK{ mi} exceeded EK{ pmi} because of the ratio of efflux clearances at the basolateral and luminal membranes for urate hippurate was less than 26.089, a value determined by the GFR, plasma renal flow, and the unbound fraction of hippurate of the system that would render E{mi} to equal E{pmi} in the system. The influx clearance for hippurate to enter from plasma to cell at the basolateral membrane and the reabsorption clearance of hippurate to enter from tubular urine to cell at the luminal membrane failed to alter the ratio of EK{ pmi}/EK{ mi}.

Footnotes

  • Send reprint requests to: Dr. K. S. Pang, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2 E-mail: pang{at}phm.utoronto.ca.

  • ↵1 This work was supported by the Medical Research Council of Canada (MA-9104).

  • Abbreviations:
    IPK
    isolated perfused rat kidney
    CLtot
    k{pmi}, urinary clearance for a preformed metabolite
    CLtot,k{mi}
    urinary clearance for a formed metabolite
    PAH
    p-aminohippurate
    HPLC
    high-performance liquid chromatography
    GFR
    glomerular filtration rate
    CIn
    steady-state input concentration
    COut
    steady-state output plasma concentration
    RBC
    red blood cell
    FE
    fractional excretion
    • Received September 29, 1997.
    • Accepted August 18, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Differences in Excretion of Hippurate, as a Metabolite of Benzoate and as an Administered Species, in the Single-Pass Isolated Perfused Rat Kidney Explained

Wanping Geng and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 597-606;

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Research ArticleArticle

Differences in Excretion of Hippurate, as a Metabolite of Benzoate and as an Administered Species, in the Single-Pass Isolated Perfused Rat Kidney Explained

Wanping Geng and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 597-606;
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