PHARMACOKINETICS AND HYPOTENSIVE EFFECT OF DEACETYL N-MONODESMETHYL DILTIAZEM (M-2) IN RABBITS AFTER A SINGLE INTRAVENOUS ADMINISTRATION

Deacetyl N-monodesmethyl diltiazem (M-2) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M-2 was a dministered as a single 5 mg/kg dose intravenously (i.v.) to New Zeala nd 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. Plas ma concentrations of M-2 were determined by HPLC. The results showed t hat there were no identifiable basic metabolites which could be quanti fied and characterized in the plasma. The apparent terminal t(1/2) and AUC were 2.8 +/- 0.7 h and 2000 +/- 290 ng.h/ml, respectively. The Cl and Clr of M-2 were 38 +/- 4.8 ml/min/kg and 0.57 +/- 0.23 ml/min/kg, respectively. M-2 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 E-max and EC50 as estimated by the inh ibitory sigmoidal E-max model were 15 +/- 7% and 450 +/- 46 ng/ml, res pectively, for SBP; 15 +/- 20% and 430 +/- 120 ng/ml for DBP.