Evaluation of the absorption, excretion, and metabolism of the antihypertensive agent RWJ-26899 in male and female CR wistar rats and beagle dogs

Abstract

The absorption, excretion and metabolism of N-(2, 6-dichlorophenyl)-beta-[[(1-methylcyclohexyl)methoxylmethyl]-N-(phenylmethyl)-1-pyrrolidineethanamine (RWJ-26899; McN-6497) has been investigated in male and female CR Wistar rats and beagle dogs. Radiolabeled [14C] RWJ-26899 was administered to rats as a single 24 mg/kg suspension dose while the dogs received 15 mg/kg capsules. Plasma (0-36 h; rat and 0-48 h; dog), urine (0-192 h; rat and dog) and fecal (0-192 h; rat and dog) samples were collected and analyzed. There were no significant gender differences observed in the data. The terminal half-life of the total radioactivity for rats from plasma was estimated to be 7.7 +/- 0.6 h while for dogs it was 22.9 +/- 4.4 h. Recoveries of total radioactivity in urine and feces for rats were 8.7 +/- 2.9% and 88.3 +/- 10.4% of the dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 4.1 +/- 1.4% and 90.0 +/- 4.7% of the dose, respectively. RWJ-26899 and a total of nine metabolites were isolated and tentatively identified in rat urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in rat urine and 8% in rat feces. RWJ-26899 and a total of four metabolites were isolated and identified in dog urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in urine and 63% in feces in dog. Five proposed pathways were used to describe the metabolites found in rats: N-oxidation, oxidative N-debenzylation, pyrrolidinyl ring hydroxylation, phenyl hydroxylation and methyl or cyclohexyl hydroxylation. Two biotransformation pathways in dogs are proposed: N-oxidation and methyl or cyclohexyl ring hydroxylation.