The steady-state pharmacokinetics and pharmacodynamics of procainamide and its active N-acetyl metabolite (NAPA) were assessed alone and in combination with trimethoprim. Eight healthy men received oral sustained-release procainamide, 500 mg every 6 hours for 3 days, alone and with oral trimethoprim, 200 mg daily for 4 days. Concomitant trimethoprim significantly increased the plasma AUC(0-12) of both procainamide and NAPA (63% and 52%, respectively), with concurrent decreases in their renal clearances (47% and 13%, respectively) and a 39% increase in the mean urinary recovery of NAPA (as percentage of procainamide and NAPA recovery). After trimethoprim coadministration, there was also a trend toward a decrease in the apparent acetylation clearance of procainamide (19%, p = 0.057). The change in procainamide and NAPA renal clearances after trimethoprim coadministration strongly correlated with their baseline renal clearances (r = 0.84 and r = 0.74, respectively, p less than 0.0001). There was small but significant increase in the corrected QT interval with procainamide administration, which increased further with trimethoprim coadministration. We conclude that trimethoprim increases the plasma concentrations of procainamide and NAPA by decreasing their renal clearances and allowing more conversion of procainamide to NAPA.