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Journal of Pharmacology And Experimental Therapeutics, Vol. 164, Issue 2, 387-395, 1968
Copyright © 1968 by American Society for Pharmacology and Experimental Therapeutics

BILIARY EXCRETION OF PROBENECID AND ITS GLUCURONIDE

ANTHONY M. GUARINO 1 and LEWIS S. SCHANKER 1

1 Laboratory of Chemical Pharmacology, National Heart institute, National Institutes of Health, Bethesda, Maryland

The carboxylic acid probenecid, administered to rats with ligated renal pedicles, readily appeared in bile as the unchanged drug and as the glucuronide of a metabolite of the drug. Twenty-five percent of a 50 mg/kg i.v. dose and 86% of a 0.1 mg/kg dose of probenecid were excreted in 90 min. The bile/plasma concentration ratio for the unchanged (free) drug was 5.1 to 14.6 at the higher dose and ranged from 87.7 to >919 for the glucuronide. These high values for the glucuronide were the result of its exceedingly low concentrations in the plasma. When the probenecid dose was increased from 22.2 to 50 mg/kg, with a resultant 2.27-fold increase in the plasma level, the proportion excreted in 90 ruin declined by about one-half, from 58% to 25%, but the amount of glucuronide excreted was unchanged (62% vs. 65%). When the dose was decreased to 0.1 mg/kg, however, about 84% appeared in the bile as the glucuronide. The phenolic acid phenolphthalein, given in a 1:1 molar ratio of inhibitor to drug, depressed the biliary concentration of free probenecid more than that of the glucuronide (by 56% vs. 11%). When the inhibitor/drug ratio was increased to 3:1, probenecid excretion decreased 79% while glucuronide excretion decreased 91%. These findings suggest that, at the low dose, phenolphthalein acted primarily on the transport of unchanged probenecid and, at the higher dose, on uridine diphosphate glucuronyl transferase.

Submitted on March 28, 1968
Accepted on August 10, 1968




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Copyright © 1968 by the American Society for Pharmacology and Experimental Therapeutics.