The effect of multiple doses of ranitidine on the pharmacokinetics and metabolism of diltiazem in dogs

In order to determine the potential pharmacokinetic drug interaction between ranitidine and diltiazem (DTZ), each of ten male beagle dogs, age 2·7–4·0 years, weight 13–16 kg, received a single oral dose of sustained release DTZ with and without previous multiple oral doses of ranitidine (150 mg bid for five doses). The dog was selected as the animal model because the pharmacokinetics and metabolism profiles of DTZ are similar to those in humans and because sustained release DTZ capsules can be administered with ease to this species. Following the oral dose of DTZ, blood samples (5 ml each) were obtained via a cephalic vein at 0 (just before dosing), 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, 36, and 48 h after the dose. Urine samples were collected for 48 h post dose. Plasma and urine concentrations of DTZ and its major metabolites N‐monodesmethyl DTZ (MA), deacetyl DTZ (M1), and deacetyl N‐monodesmethyl DTZ (M2) were determined by HPLC. Pharmacokinetic parameters were calculated by non‐linear curve fitting, and the effect of ranitidine was evaluated by two‐factor analysis of variance (ANOVA). Pre‐treatment of the animals did not significantly alter the disposition of DTZ (p >0·05). Similar to the results reported in clinical studies, there were large variations in the plasma and urine concentrations of DTZ and its major metabolites among the beagle dogs. The effect of ranitidine on the disposition of DTZ was highly variable.