Evaluation of the excretion and metabolism of the new analgesic agent RWJ-22757 in male and female CR Wistar rats

Abstract

The excretion and metabolism of (±)- trans-3-(2-bromophenyl)octahydroindolizine hydrochloride (RWJ-22757) have been investigated in male and female CR Wistar rats. Radiolabeled [ 14C] RWJ-22757 was administered orally to each of the rats as a single 60 mg/kg suspension dose. Plasma (0–48 h), urine (0–168 h) and fecal (0–168 h) samples were collected and analyzed. There were no significant gender differences observed in the data. The estimated elimination half-life of the total radioactivity from plasma was 19 h while the estimated elimination half-life of RWJ-22757 was 15 h. Recoveries of total radioactivity in urine and feces were 58.4±5.8 and 42.4±6.3%, respectively. RWJ-22757 and a total of 11 metabolites were isolated in rat plasma, urine, and fecal extracts. The structures of four of these metabolites were tentatively identified. Unchanged RWJ-22757 accounted for <4% of the dose in plasma and urine and 28% in feces; thus, indicating the drug was extensively metabolized and either not absorbed well or biliary excreted. Identified metabolites accounted for >80% of the total radioactivity contained in the samples. The following pathways were used to describe the formation of the metabolites identified in rats: octahydroindolizine ring oxidation, phenyl hydroxylation, octahydroindolizine ring oxidation followed by ring opening to a carboxylic acid function and octahydroindolizine ring oxidation followed by ring opening and N-methylation.