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Title: Metabolism and excretion of RWJ-333369 in mice, rats, rabbits, and dogs
Authors: Mamidi, Rao N V S ×
Mannens, Geert
Annaert, Pieter
Hendrickx, Jan
Goris, Ivo
Bockx, Mark
Janssen, Cor G M
Kao, Mark
Kelley, Michael F
Meuldermans, Willem #
Issue Date: Apr-2007
Publisher: American Society for Pharmacology and Experimental Therapeutics
Series Title: Drug metabolism and disposition vol:35 issue:4 pages:566-75
Abstract: The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulphate conjugation (either directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.
ISSN: 0090-9556
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Drug Delivery and Disposition
× corresponding author
# (joint) last author

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