| The administration of H2 receptor antagonists such as cimetidine, ranitidine, and famotidine have been used in treatment of ulcers for a number of years. Effects of H2 antagonists on basal gastric pH, free and total acid content as well as clinical efficacy for treatment of gastric ulcers has been determined. Experiments were designed to determine the pharmacokinetics and bioavailability of cimetidine, ranitidine and famotidine. Three groups of five adult horses in each group were administered intravenous (IV) doses of 3.3 mg/kg, 5 mg/kg, and 0.5 mg/kg of cimetidine, ranitidine and famotidine, respectively. One month later, the same horses in each group received an oral dose of 10 mg/kg cimetidine, 40 mg/kg ranitidine and 1 mg/kg famotidine. Blood samples were taken from each horse over a 24 hour period at times appropriate for pharmacokinetic study. Plasma was extracted and stored at -80°C, then analyzed using modified high pressure liquid chromatography (HPLC) methods specific to each drug and validated (95 +/- 5%) in animal specific plasma. Plasma concentrations versus time data after IV administration of cimetidine, ranitidine and famotidine were evaluated by multi-compartmental modeling. The half-lives of these three drugs IV ranged from 2.12 to 2.52 hours with no significant difference. Total body clearance of IV and oral famotidine was statistically greater than ranitidine or cimetidine. The greatest difference seen IV or oral in these drugs was the volume of distribution (Vd). Famotidine having the highest Vd, then ranitidine and lowest was cimetidine. Half-lives after oral dosing were similar among drugs as compared to half-lives observed in the IV studies. Bioavailability of all three drugs was low with marked variation from horse to horses. IV is the preferred route.; Other experiments were designed to determine the pharmacokinetics, and bioavailability of ranitidine in cats, dogs and sheep. Pharmacodynamic studies were also performed in dogs and sheep. In different studies, separate groups of dogs received prednisone and ranitidine, and prednisone, saline, and ranitidine to compare the gastric ulcer healing of ranitidine in dogs treated with prednisone.; The half-lives of ranitidine IV were compared among the four species studied, sheep (3.74 hours) having the longest, horse (2.52 hours), cats (1.65 hours), to the dog with the shortest (1.023 hours). Clearance was highest in the dog (1.92 L/hr/kg) and shortest in the horse (0.59 L/hr/kg). The volume of distribution was highest in the sheep (5.74 L/kg) and lowest in the horse (2.14 L/kg). Bioavailability was much higher in the cat (0.661 +/- 0.105), and sheep (0.62 +/- 0.425) than in the horse (0.135 +/- 0.5). In both the dog and sheep study, pH of stomach and abomasal contents were measured, respectively. The pH increased in each gastrointestinal compartment due to the effects of ranitidine. Dogs receiving ranitidine plus prednisone had a delay of an onset of gastric ulcers as versus the prednisone group, but by day four, there was no statistical difference of gastric ulcer formation. IV administration to the dogs in the ranitidine plus prednisone group for the first dose may account for the delay. IV is the preferred route for all studies. |
