OBJECTIVE To investigate the effect of cimetidine and probenecid on the renal 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 1,500 mg oral probenecid on three occasions in a Latin-square order. Urine and venous blood samples were collected on a timely basis. The concentration of pilsicainide in plasma and urine were determined by an HPLC method. RESULTS Concomitant administration of cimetidine significantly increased the 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 hours), reduced apparent oral clearance by a mean of 26% (from 14.7 +/- 0.1 to 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 secretion was significantly reduced by a mean value of 38%, from 151.4 +/- 62.9 to 93.0 +/- 31.1 mL/min. Coadministration of probenecid did not show any changes in plasma concentrations of pilsicainide, pharmacokinetics, or the net renal clearance by tubular secretion of pilsicainide. CONCLUSIONS Pilsicainide appeared to be secreted by the active transport system for organic bases in the proximal tubule, and the excretion of pilsicainide was inhibited by cimetidine.