Effect of Administration Route and Length of Exposure on Pharmacokinetics and Metabolism of Diltiazem in Dogs

The objective of this study was to systematically determine the pharmacokinetics and metabolism of diltiazem (DTZ) after a single i.v. dose, and after single and multiple oral (p.o.) doses. Four mongrel dogs (3 M, 1 F), aged 1-3 years, body weight 19-25 kg, were each given a single 30 mg dose of DTZ as a solution by i.v injection, the same dose orally from an immediate release tablet (Cardizem, Aventis Pharma, Canada, QC), and also t.i.d. for 10 doses. A 3-4 week washout period was allowed between each treatment. Blood samples (4 ml each) were obtained after each treatment from each animal via a cephalic vein at 0 (just before dosing), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, and 12.0 h post dose. Urine samples were collected for 24 h. The plasma samples were immediately separated by centrifugation and stored at -20 degrees C until analysis. The results showed that the bioavailability after a single p.o. dose of DTZ was 26+/-24%. Following a single i.v. dose, DTZ declined bi-exponentially with a terminal half-life (t1/2) of 4.2+/-1.7 h. N-Monodesmethyl DTZ (M(A)), deacetyl DTZ (M1), and deacetyl N-monodesmethyl DTZ (M2) were the major metabolites. Contrary to the results observed in clinical studies, there were no increase of plasma concentrations of DTZ after repeated doses (accumulation factor R = 0.94+/-0.51). Plasma concentrations of M1 decreased following repeated oral doses, accompanying by an increase of plasma concentrations of M2, although these changes were not statistically significant (p >0.05). This study cautions the use of mongrel dogs for direct extrapolation to humans, particularly for chronic pharmacokinetics studies of DTZ.