RT Journal Article SR Electronic T1 The Absorption, Metabolism, and Excretion of the Novel Neuromodulator RWJ-333369 (1,2-Ethanediol, [1-2-Chlorophenyl]-, 2-carbamate, [S]-) in Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 554 OP 565 DO 10.1124/dmd.106.011940 VO 35 IS 4 A1 G. S. J. Mannens A1 J. Hendrickx A1 C. G. M. Janssen A1 S. Chien A1 B. Van Hoof A1 T. Verhaeghe A1 M. Kao A1 M. F. Kelley A1 I. Goris A1 M. Bockx A1 B. Verreet A1 M. Bialer A1 W. Meuldermans YR 2007 UL http://dmd.aspetjournals.org/content/35/4/554.abstract AB 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 14C-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. The American Society for Pharmacology and Experimental Therapeutics