title: Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.
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 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.
authors.affiliation: Preclinical Drug Development, OMP-2211, Johnson & Johnson Pharmaceutical Research & Development, 1000 US 202 S, Raritan, NJ 08807, USA. smamidi1@prdus.jnj.com
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Geert
authors.initials: G
authors.lastname: Mannens
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.forename: Jan
authors.initials: J
authors.lastname: Hendrickx
authors.forename: Ivo
authors.initials: I
authors.lastname: Goris
authors.forename: Mark
authors.initials: M
authors.lastname: Bockx
authors.forename: Cor G M
authors.initials: CG
authors.lastname: Janssen
authors.forename: Mark
authors.initials: M
authors.lastname: Kao
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kelley
authors.forename: Willem
authors.initials: W
authors.lastname: Meuldermans
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting; D013463:Sulfuric Acid Esters / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D002250:Carbon Radioisotopes; D020719:Glucuronides; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D013463:Sulfuric Acid Esters