Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M-1) 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-1 was administered as a single 5 mg kg(-1) dose intravenously (iv) 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 M-1 and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M-2). The t(1/2) and AUC of M-1 and M-2 were 2.1 +/- 0.5 and 3.0 +/- 1.1 h, and 1300 +/- 200 and 240 +/- 37 ng h mL(-1), respectively. The Cl and Cl-r of M-1 were 60 +/- 10 and 0.81 +/- 0.63 mL min(-1) kg(-1), respectively. M-1 significantly decreased blood pressure (SBP and DBP) for up to 1 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 inhibitory sigmoidal E-max model were 20 +/- 18% 620 +/- 310 ng mL(-1), respectively for SEP; 20 +/- 8.3% and 420 +/- 160 ng mL(-1) for DBP. (C) 1998 John Wiley & Sons, Ltd.