Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.
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.
Mamidi
Rao N V S
RN
Preclinical Drug Development, OMP-2211, Johnson & Johnson Pharmaceutical Research & Development, 1000 US 202 S, Raritan, NJ 08807, USA. smamidi1@prdus.jnj.com
Mannens
Geert
G
Annaert
Pieter
P
Hendrickx
Jan
J
Goris
Ivo
I
Bockx
Mark
M
Janssen
Cor G M
CG
Kao
Mark
M
Kelley
Michael F
MF
Meuldermans
Willem
W
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
D000927:Anticonvulsants; D002219:Carbamates; D002250:Carbon Radioisotopes; D020719:Glucuronides; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D013463:Sulfuric Acid Esters