SATURABLE URINARY-EXCRETION KINETICS OF FAMOTIDINE IN THE DOG

An important elimination route of the histamine H-2 antagonist famotid ine is active tubular secretion via the renal organic cation transport system. To characterize the excretion kinetics of famotidine in-vivo, the relationship between plasma concentration and urinary excretion r ate was investigated in the beagle dog over a wide concentration range . The maximum transport capacity and the apparent Michaelis-Menten con stant of tubular secretion were estimated. Concentration-dependent ren al clearance was determined either after intravenous infusion of high doses of famotidine for a short time or during continuous infusion. Fr om individual experiments only indications of saturation were observed ; these could not be quantified. A tubular titration curve, in which t he active tubular famotidine secretion was plotted against the plasma concentration, was constructed from the data from all the experiments. Active tubular secretion was calculated for each experiment separatel y by subtracting the famotidine filtration rate from the total excreti on rate. A tubular transport maximum of 2400 +/- 220 mu g min(-1) and an apparent Michaelis-Menten constant for tubular secretion of 26 +/- 4 mu g mL(-1) (76 +/- 12 mu M) were estimated from the curve. To the b est of our knowledge, this is the first time that saturation of famoti dine renal clearance has been fully quantified in-vivo. Considering th e low therapeutic plasma concentrations of famotidine (< 0.1 mu g mL(- 1)), these results suggest that clinically the drug has a low interact ive potential.