PT - JOURNAL ARTICLE AU - Stacey L. Polsky-Fisher AU - Stanley Vickers AU - Donghui Cui AU - Raju Subramanian AU - Byron H. Arison AU - Nancy G. B. Agrawal AU - Thanh V. Goel AU - Laura K. Vessey AU - M. Gail Murphy AU - Kenneth C. Lasseter AU - Richard C. Simpson AU - Jose M. Vega AU - A. David Rodrigues TI - METABOLISM AND DISPOSITION OF A POTENT AND SELECTIVE GABA-A<sub>α2/3</sub> RECEPTOR AGONIST IN HEALTHY MALE VOLUNTEERS AID - 10.1124/dmd.105.008193 DP - 2006 Jun 01 TA - Drug Metabolism and Disposition PG - 1004--1011 VI - 34 IP - 6 4099 - http://dmd.aspetjournals.org/content/34/6/1004.short 4100 - http://dmd.aspetjournals.org/content/34/6/1004.full SO - Drug Metab Dispos2006 Jun 01; 34 AB - [14C]7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine ([14C]-TPA023; 99 μCi/dose) was administered to five young, healthy, fasted male subjects as a single oral dose (3.0 mg) in solution (propylene glycol/water, 10:90 v/v). The parent compound was rapidly absorbed (plasma Tmax ∼2 h), exhibited an apparent terminal half-life of 6.7 h, and accounted for approximately 53% of the total radioactivity in plasma. After 7 days of collection, the mean total recovery of radioactivity in the excreta was 82.6%, with 53.2% and 29.4% in urine and feces, respectively. Radiochromatographic analysis of the excreta revealed that TPA023 was metabolized extensively, and only trace amounts of unchanged parent were recovered. Radiochromatograms of urine and feces showed that TPA023 underwent metabolism via three pathways (t-butyl hydroxylation, N-deethylation, and direct N-glucuronidation). The products of t-butyl hydroxylation and N-deethylation, together with their corresponding secondary metabolites, accounted for the majority of the radioactivity in the excreta. In addition, approximately 10.3% of the dose was recovered in urine as the triazolo-pyridazine N1-glucuronide of TPA023. The t-butyl hydroxy and N-desethyl metabolites of TPA023, the TPA023 N1-glucuronide, and the triazolo-pyridazine N1-glucuronide of N-desethyl TPA023 were present in plasma. In healthy male subjects, therefore, TPA023 is well absorbed and is metabolized extensively (t-butyl hydroxylation and N-deethylation &gt; glucuronidation), and the metabolites are excreted in urine and feces. The American Society for Pharmacology and Experimental Therapeutics