PHARMACOKINETICS AND HEMODYNAMIC-EFFECT OF DEACETYL DILTIAZEM (M-1) IN RABBITS AFTER A SINGLE INTRAVENOUS ADMINISTRATION

Deacetyl diltiazem (M-1) is a major metabolite of the widely used calc ium 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 rabbi ts (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabb it up to 8 h, and urine samples for 48 h post-dose. Plasma concentrati ons of M-1 and its metabolites were determined by HPLC. The results sh owed that the only quantifiable basic metabolite in the plasma was dea cetyl N-monodesmethyl DTZ (M-2). The t(1/2) and AUC of M-1 and M-2 wer e 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 b lood pressure (SBP and DBP) for up to 1 h post-dose (p < 0.05), but ha d no significant effect on the heart rate (p > 0.05). The E-max and EC 50 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.