RT Journal Article SR Electronic T1 METABOLISM AND DISPOSITION OF A POTENT AND SELECTIVE GABA-Aα2/3 RECEPTOR AGONIST IN HEALTHY MALE VOLUNTEERS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1004 OP 1011 DO 10.1124/dmd.105.008193 VO 34 IS 6 A1 Stacey L. Polsky-Fisher A1 Stanley Vickers A1 Donghui Cui A1 Raju Subramanian A1 Byron H. Arison A1 Nancy G. B. Agrawal A1 Thanh V. Goel A1 Laura K. Vessey A1 M. Gail Murphy A1 Kenneth C. Lasseter A1 Richard C. Simpson A1 Jose M. Vega A1 A. David Rodrigues YR 2006 UL http://dmd.aspetjournals.org/content/34/6/1004.abstract 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 > glucuronidation), and the metabolites are excreted in urine and feces. The American Society for Pharmacology and Experimental Therapeutics