Absorption and disposition of ranitidine hydrochloride in rat and dog

Abstract

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 Cl_r accounting for approximately 30% of total clearance. Vd_area was 3·51/kg, resulting in a t_1/2 of approximately 4 h.

3. After oral administration, F was good (73%) with peak plasma concentrations of ranitidine (2 μg/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 [¹⁴C]-ranitidine were studied in rat and dog after oral administration at a dose level of 50 mg/kg.

5. Urinary excretion was the major elimination pathway for radioactive drug-related material in both species (62–75% of the dose). Unchanged ranitidine was the major radioactive component in both rat and dog urine (0–24 h), accounting for approximately 40% of the dose in each case.

6. In dog, ranitidine undergoes N-oxidation (∼ 30% of dose) whereas in rat, N-oxidation, S-oxidation, N-demethylation and oxidative deamination are all evident, with each metabolite accounting for <6% of the dose.

7. Two previously unreported metabolites of ranitidine were identified in rat urine using newly developed hplc and lc/ms methods. These metabolites result from single and di-N-demethylation of ranitidine and accounted for 4 and 1% of the dose respectively.