Effect of H2 antagonists on the differential secretion of triamterene and its sulfate conjugate metabolite by the isolated perfused rat kidney

Abstract

The isolated perfused rat kidney model was used to examine the effect of the histamine H2 antagonists cimetidine, ranitidine, and famotidine and the organic anion inhibitor probenecid on the differential renal handling of triamterene and its active metabolite p-hydroxytriamterene sulfate. The kidneys were perfused with a Krebs-Henseleit buffer containing albumin, glucose, and amino acids to pH 7.4, and drug concentrations were measured by HPLC. At an initial triamterene concentration of 0.5 mg/liter, the unbound renal clearance to glomerular filtration rate (GFR) ratio was 11.0 +/- 2.5 (mean +/- SD): 1, indicating substantial tubular secretion of the drug. Cimetidine and ranitidine reduced the tubular secretion by about 80% (p less than 0.01), famotidine by between 35 and 60% (p = 0.05), whereas probenecid had no inhibitory effect. For p-hydroxytriamterene sulfate, its unbound renal clearance to GFR ratio was 41 +/- 25:1; this was not affected by cimetidine, ranitidine, or famotidine, whereas probenecid significantly (p less than 0.01) reduced the rate of tubular secretion by 80%. These data indicate that the renal tubular secretion of triamterene is mediated by the organic cation system, whereas for p-hydroxytriamterene sulfate its tubular secretion is via the organic anion system. Famotidine is a weaker inhibitor of the organic cation system compared with cimetidine and ranitidine. These results have implications for drug-drug interaction studies involving renal elimination pathways.