Metabolism and Excretion of RWJ-333369 [1,2-Ethanediol, 1-(2-Chlorophenyl)-, 2-carbamate, (S)-] in Mice, Rats, Rabbits, and Dogs

• Published in: Drug metabolism and disposition Vol. 35; no. 4; pp. 566 - 575
• Main 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
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-04-2007
• Subjects: Administration, Oral; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; Anticonvulsants - urine; Biological and medical sciences; Biotransformation; Carbamates - administration & dosage; Carbamates - blood; Carbamates - pharmacokinetics; Carbamates - urine; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Dogs; Feces - chemistry; Female; Glucuronides - metabolism; Hydrolysis; Kidney - metabolism; Male; Medical sciences; Mice; Molecular Structure; Oxidation-Reduction; Pharmacology. Drug treatments; Rabbits; Rats; Rats, Sprague-Dawley; Scintillation Counting; Sulfuric Acid Esters - metabolism; Tandem Mass Spectrometry; Fissipedia; Carnivora; Excretion; Rat; Rodentia; Rabbit; Lagomorpha; Metabolism; Vertebrata; Mammalia; Mouse; Animal; Pharmacokinetics; Dog; Carbamate
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.106.012336

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 sulfate conjugation (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.