Yeung P K, Feng J D, Buckley S J
Pharmacokinetics and Metabolism Laboratory, College of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada.
Biopharm Drug Dispos. 1998 Mar;19(2):109-13. doi: 10.1002/(sici)1099-081x(199803)19:2<109::aid-bdd84>3.0.co;2-v.
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 (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 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), 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 20 +/- 18% 620 +/- 310 ng mL-1, respectively for SBP; 20 +/- 8.3% and 420 +/- 160 ng mL-1 for DBP.
