title: Effect of administration route and length of exposure on pharmacokinetics and metabolism of diltiazem in dogs.
abstract: 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.
authors.affiliation: College of Pharmacy & Department of Medicine, Faculty of Health Professions, Dalhousie University, Halifax, Nova Scotia, Canada. Pollen.Yeung@Dal.Ca
authors.forename: P K
authors.initials: PK
authors.lastname: Yeung
authors.forename: J D
authors.initials: JD
authors.lastname: Feng
authors.forename: S J
authors.initials: SJ
authors.lastname: Buckley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood*; D004110:Diltiazem / Q000008:administration & dosage / Q000097:blood*; D004285:Dogs; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male
chemical_list: D002317:Cardiovascular Agents; D004110:Diltiazem