PT  - JOURNAL ARTICLE
AU  - Mannens, G. S. J.
AU  - Hendrickx, J.
AU  - Janssen, C. G. M.
AU  - Chien, S.
AU  - Van Hoof, B.
AU  - Verhaeghe, T.
AU  - Kao, M.
AU  - Kelley, M. F.
AU  - Goris, I.
AU  - Bockx, M.
AU  - Verreet, B.
AU  - Bialer, M.
AU  - Meuldermans, W.
TI  - The Absorption, Metabolism, and Excretion of the Novel Neuromodulator RWJ-333369 (1,2-Ethanediol, [1-2-Chlorophenyl]-, 2-carbamate, [<em>S</em>]-) in Humans
AID  - 10.1124/dmd.106.011940
DP  - 2007 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 554--565
VI  - 35
IP  - 4
4099  - http://dmd.aspetjournals.org/content/35/4/554.short
4100  - http://dmd.aspetjournals.org/content/35/4/554.full
SO  - Drug Metab Dispos2007 Apr 01; 35
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