This study was designed to determine the pharmacokinetics and dose proportionality of clentiazem (CLZ) after single doses (SD) of 20, 40, and 80 mg and multiple dose administration (SS) of 40, 80, and 160 mg/day for 5 days. The study was an open-label, randomized four-period complete crossover design. Twenty-four healthy male volunteers participated in the study, and blood samples were drawn over 48 hours after both SD and SS. Plasma samples were analyzed for CLZ and three metabolites by high-pressure liquid chromatography. After SD, the area under the plasma concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) increased disproportionately with the increase in dose. At steady-state, a twofold increase in dose (20 to 40 mg twice daily and 40 to 80 mg twice daily) resulted in an increase in AUCss of 2.14- and 2.51-fold, respectively. Oral clearance of CLZ decreased (203.8 L/h at 40 mg/d to 140.2 L/h at 160 mg/d) and bioavailability increased (0.35 at 40 mg/d to 0.50 at 160 mg/d) with increasing doses. The terminal half-life of CLZ remained unchanged with increasing doses (13.7-15.5 hours). The ratios of AUCss to AUC0-infinity at SD ranged from 1.13 to 1.27, indicating no significant accumulation of CLZ (P > .05). The AUC ratio of N-desmethyl CLZ to that of CLZ remained constant after SD. On SS, however, there was a small decrease in this ratio with increasing dose (0.77 at 40 mg/d to 0.61 at 160 mg/d). These results indicate that the degree of nonlinearity observed with CLZ pharmacokinetics may largely be due to saturable first-pass metabolism.