The once-daily formulation of diltiazem hydrochloride (Cardizem CD) is marketed for the treatment of essential hypertension and stable angina pectoris. The steady-state pharmacokinetics of once-daily diltiazem and its metabolites, desacetyldiltiazem (DAD) andN-desmethyldiltiazem (MA), were examined in two groups of eight healthy subjects each. The first group (group A) received 240, 480, and 720 mg diltiazem once daily for 7 days in a single-blind, stair-step, dose-escalation design. The second group (group B) received 180, 360, and 720 mg diltiazem in a similar manner. At each dose level, serial blood samples were collected for up to 24 hours after the last (seventh) dose. Plasma samples were analyzed for diltiazem and the metabolites by high-performance liquid chromatography. The disposition of diltiazem, DAD, and MA was nonlinear over the 240− to 720-mg (group A) and 180− to 720-mg (group B) diltiazem dose ranges studied. In group A, mean diltiazem area under the plasma concentration-time curve (AUC) at the 240-mg dose level was 2410 h-ng/mL compared with 10,167 h-ng/mL at the 720-mg dose level. In group B, mean diltiazem AUC at the 180-mg dose level was 1092 h-ng/mL compared with 8398 h-ng/mL at the 720-mg dose level. The apparent oral clearance decreased 35% over a threefold dose range (group A) and 51% over a fourfold dose range (group B). Mean ratios of AUCDAD/AUCDILTwere similar at all dose levels. Mean AUCMA/AUCDILTratios, however, decreased with increasing diltiazem dose, suggesting that the nonlinear disposition of MA may be less pronounced than that of parent drug.