ABSORPTION AND DISPOSITION OF RANITIDINE HYDROCHLORIDE IN RAT AND DOG

1. The pharmacokinetics of ranitidine were studied in the male beagle dog at a dose level of 50 mg (intravenous) or 5 mg/kg (oral). 2. After intravenous administration, Cl-p was moderate (10.4 ml/min/kg) with C l-r accounting for approximately 30% of total clearance. V-darea was 3 .5 1/kg, resulting in a t(1/2) of approximately 4 h. 3. After oral adm inistration, F was good (73%) with peak plasma concentrations of ranit idine (2 mu g/ml) achieved within 0.5-1 h after dosing. t(1/2) (4.1 h) was similar to that observed after intravenous administration. 4. The absorption, metabolism and excretion of [C-14]-ranitidine were studie d in rat and dog after oral administration at a dose level of 50 mg/kg . 5. Urinary excretion was the major elimination pathway for radioacti ve drug-related material in both species (62-75% of the dose). Unchang ed ranitidine was the major radioactive component in both rat and dog urine (0-24 h), accounting for approximately 40% of the dose in each c ase. 6. In dog, ranitidine undergoes N-oxidation (similar to 30% of do se) whereas in rat, N-oxidation, S-oxidation, N-demethylation and oxid ative deamination are all evident, with each metabolite accounting for < 6% of the dose. 7. Two previously unreported metabolites of ranitid ine were identified in rat urine using newly developed hplc and lc/ms methods. These metabolites result from single and di-N-demethylation o f ranitidine and accounted for 4 and 1% of the dose respectively.