QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.008193v1 34/6/1004    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Polsky-Fisher, S. L. Articles by Rodrigues, A. D. Search for Related Content PubMed PubMed Citation Articles by Polsky-Fisher, S. L. Articles by Rodrigues, A. D.

METABOLISM AND DISPOSITION OF A POTENT AND SELECTIVE GABA-A_2/3 RECEPTOR AGONIST IN HEALTHY MALE VOLUNTEERS

Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey (S.L.P.-F., S.V., D.C., R.S., B.H.A., N.G.B.A., T.V.G., R.C.S., A.D.R.); Clinical Pharmacology, Merck Research Laboratories, Blue Bell, Pennsylvania (L.K.V., M.G.M., J.M.V.); and Clinical Pharmacology Associates, Miami, Florida (K.C.L.)

[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 T_max 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.

This article has been cited by other articles:

				B. Ma, S. L. Polsky-Fisher, S. Vickers, D. Cui, and A. D. Rodrigues Cytochrome P450 3A-Dependent Metabolism of a Potent and Selective {gamma}-Aminobutyric AcidA{alpha}2/3 Receptor Agonist in Vitro: Involvement of Cytochrome P450 3A5 Displaying Biphasic Kinetics Drug Metab. Dispos., August 1, 2007; 35(8): 1301 - 1307. [Abstract] [Full Text] [PDF]