In order to study the effect of cytochrome P-450 isozyme induction on the pharmacokinetics and metabolism of diltiazem (DTZ), male Sprague-Dawley rats weighing 300-600 g were randomly assigned to two groups. The enzyme induction group (n = 4) received phenobarbital 60 mg/kg i.p. once daily for 4 days, whereas the control group (n = 6) received normal saline for the same duration. Each rat then received a single oral dose of DTZ in solution (20 mg/kg). Blood samples (0.5 ml) were collected from each rat via an implanted polyethylene catheter (0.040" i.d.) in the right carotid artery at 0 (just before dosing), 0.25, 0.5, 1,2,3,4,6,8 and 10 h post-dose. Arterial plasma concentrations of DTZ and its metabolites M(A), M1, M2, M4 and M6 were determined by HPLC. Pharmacokinetics parameters were calculated using non-linear regression. The results showed that both mean Cmax and AUC of DTZ were lower (871.6 vs 79.8 ng/ml; 1171 vs 101.9 ng-h/ml), but the mean Cmax of the primary metabolites M1 and M(A) was higher after phenobarbital (M1 413.0 vs 648.9 ng/ml; M(A) 683.0 vs 814.8 ng/ml). The highest increase was seen in the mean Cmax and AUC of the secondary metabolite M2 (837.5 vs 2585.7 ng/ml; 3312.1 vs 13156.5 ng-h/ml). In contrast, plasma concentrations of the O-desmethylated metabolites M4 and M6 did not increase after phenobarbital. These results suggest that both deacetylation and N-demethylation of DTZ in rats are catalyzed by drug metabolizing enzymes inducible by phenobarbital.