Pharmacokinetics and hypotensive effect of deacetyl N-monodesmethyl diltiazem (M2) in rabbits after a single intravenous administration

Abstract

Deacetyl N-monodesmethyl diltiazem (M2) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M2 was administered as a single 5 mg/kg dose intravenously (i.v.) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M2 were determined by HPLC. The results showed that there were no identifiable basic metabolites which could be quantified and characterized in the plasma. The apparent terminal t1/2 and AUC were 2.8 +/- 0.7 h and 2000 +/- 290 ng x h/ml, respectively. The Cl and Clr of M2 were 38 +/- 4.8 ml/min/kg and 0.57 +/- 0.23 ml/min/kg, respectively. M2 significantly decreased blood pressure (SBP and DBP) for up to 2 h post-dose (P < 0.05), but had no significant effect on the heart rate (P > 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 15 +/- 7% and 450 +/- 46 ng/ml, respectively, for SBP; 15 +/- 20% and 430 +/- 120 ng/ml for DBP.