Pharmacokinetics and hypotensive effect of diltiazem in rabbits: Comparison of diltiazem with its major metabolites

To assess the contribution of its metabolites to the antihypertensive effec ts of diltiazem, a previously established rabbit model has been used to com pare the pharmacokinetics and haemodynamic effects of the drug with those o f its major metabolites deacetyldiltiazem (M-1) and deacetyl-N-monodemethyl diltiazem (M-2). Diltiazem, M-1 and M-2 were administered separately to each animal (n = 5 o r 6 per study group) as a single 5 mg kg(-1) intravenous dose. Blood sample s, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to sh, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites w ere determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vd(ss)) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SEP a nd DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent th an M1 or MZ, possibly because of the higher plasma concentrations secondary to the smaller CL and Vd(ss) of diltiazem compared with the metabolites. T he effects of the metabolites might, however, be more sustained.