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

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Summary

The absorption, excretion and metabolism of N-(2,6-dichlorophenyl)-β-[[(1-methylcyclohexyl)methoxy]methyl]-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, phenylhydroxylation and methyl or cyclohexyl hydroxylation. Two biotransformation pathways in dogs are proposed: N-oxidation and methyl or cyclohexylring hydroxylation.

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Authors and Affiliations

  1. Division of Preclinical Development, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, 19477, Spring House, PA, USA

    W. N. Wu

  2. Division of Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, Spring House, PA, USA

    G. W. Caldwell & J. A. Masucci

Authors
  1. W. N. Wu
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  2. G. W. Caldwell
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  3. J. A. Masucci
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Correspondence to G. W. Caldwell.

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Wu, W.N., Caldwell, G.W. & Masucci, J.A. Evaluation of the absorption, excretion, and metabolism of the antihypertensive agent RWJ-26899 in male and female CR wistar rats and beagle dogs. Eur. J. Drug Metab. Pharmacokinet. 26, 155–166 (2001). https://doi.org/10.1007/BF03190391

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  • DOI: https://doi.org/10.1007/BF03190391

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