Effect of cimetidine and probenecid on pilsicainide renal clearance in humans

Objective: To investigate the effect of cimetidine and probenecid on the re nal clearance of pilsicainide in healthy subjects. Methods: Nine healthy men (age range, 21 to 38 years) were given oral doses of 50 mg pilsicainide hydrochloride alone, with coadministration of 800 mg oral cimetidine, or with coadministration of 1500 mg oral probenecid on th ree occasions in a Latin-square order, Urine and venous blood samples were collected on a timely basis. The concentration of pilsicainide in plasma an d urine were determined by an HPLC method. Results: Concomitant administration of cimetidine significantly increased t he area under the plasma concentration-time curve of pilsicainide by a mean of 33%, prolonged elimination half-life by a mean of 24% (from 5 to 6.2 ho urs), reduced apparent oral clearance by a mean of 26% (from 14.7 +/- 0.1 t o 10.8 +/- 0.8 L/h) and reduced renal clearance by a mean of 28% (from 196. 8 +/- 53.9 to 141.8 +/- 25.9 mL/min). The net renal clearance by tubular se cretion was significantly reduced by a mean value of 38%, from 151.4 +/- 62 .9 to 95.0 +/- 31.1 mL/min. Coadministration of probenecid. did not show an y changes in plasma concentrations of pilsicainide, pharmacokinetics, or th e net renal clearance by tubular secretion of pilsicainide. Conclusions; Pilsicainide appeared to be secreted by the active transport s ystem for organic bases in the proximal tubule, and the excretion of pilsic ainide was inhibited by cimetidine.