Famotidine is a new histamine H2-receptor antagonist which has been demonstrated to be more potent than cimetidine and ranitidine in inhibiting gastric acid secretion. Nine groups of adult male Sprague-Dawley rats received an ia injection of various loading doses of famotidine followed immediately by a constant infusion of the drug at different rates for 6 hr. When steady state famotidine concentrations in plasma were low, renal clearance of the drug (CLR) was greater than glomerular filtration (GFR), and the ratio CLR/GFR was about 4.5 at plasma concentrations of 0.2-1.8 micrograms/ml, suggesting that famotidine was actively secreted by the renal tubules. The CLR decreased as famotidine concentration in plasma increased, and the ratio CLR/GFR approached 1 in the concentration range of 25-76 micrograms/ml, thus providing evidence for saturation of the secretory mechanism. The maximum rate of secretory transport (Tm) of famotidine averaged 180 micrograms/min/kg. On average, some 50-70% of an ia bolus dose was excreted in the urine as unchanged drug within 24 hr of administration. Over the dose range of 0.3-30 mg/kg famotidine, there was no dose-dependent effect on total or renal clearance. Since the lowest dose level, 0.3 mg/kg, is below the recommended human therapeutic dose for famotidine (0.6 mg/kg), the saturation of the renal excretion process observed here in rats is not likely to be of clinical significance.