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

Deacetyl diltiazem (M1) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M1 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 M1 and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N‐monodesmethyl DTZ (M2). The t1/2 and AUC of M1 and M2 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 Clr of M1 were 60±10 and 0.81±0.63 mL min−1 kg−1, respectively. M1 significantly decreased blood pressure (SBP and DBP) for up to 1 h post‐dose (p 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 20±18% 620±310 ng mL−1, respectively for SBP; 20±8.3% and 420±160 ng mL−1 for DBP. © 1998 John Wiley & Sons, Ltd.