The Absorption, Metabolism, and Excretion of the Novel Neuromodulator RWJ-333369 (1,2-Ethanediol, [1-2-Chlorophenyl]-, 2-carbamate, [ S ]-) in Humans

• DOI: 10.1124/dmd.106.011940
• Publication Date: 2006-08-26T02:57:57Z
• Authors: G.S.J. Mannens; J. Hendrickx; C.G.M. Janssen; S. Chien; B. Van Hoof; T. Verhaeghe; M. Kao; M.F. Kelley; I. Goris; M. Bockx; B. Verreet; M. Bialer; W. Meuldermans
• Keywords: Adult; Male; Administration, Oral; Sulfuric Acid Esters; Kidney; Feces; 03 medical and health sciences; Glucuronides; 0302 clinical medicine; Reference Values; Tandem Mass Spectrometry; Humans; Biotransformation; Chromatography, High Pressure Liquid; Molecular Structure; Hydrolysis; Middle Aged; 6. Clean water; 3. Good health; Intestinal Absorption; Uridine Diphosphate Glucuronic Acid; Anticonvulsants; Carbamates; Oxidation-Reduction

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.