The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans
| Autor: | Willem Meuldermans, Geert Mannens, B. Verreet, Marc Bockx, M. Bialer, B. Van Hoof, Tom Verhaeghe, Mark L. Kao, Michael F. Kelley, S. Chien, J. Hendrickx, Cor G. M. Janssen, I. Goris |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Carbamate medicine.medical_treatment Pharmaceutical Science Administration Oral Urine Sulfuric Acid Esters Kidney Excretion Feces Glucuronides Pharmacokinetics Reference Values Tandem Mass Spectrometry medicine Humans Mercapturic acid Biotransformation Chromatography High Pressure Liquid Pharmacology Chromatography Molecular Structure Chemistry Hydrolysis Metabolism Middle Aged Intestinal Absorption Glycine Uridine Diphosphate Glucuronic Acid Anticonvulsants Carbamates Oxidation-Reduction |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 35(4) |
| ISSN: | 0090-9556 |
| Popis: | 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 (each0.3% 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. |
| Databáze: | OpenAIRE |
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