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First published on March 1, 2006; DOI: 10.1124/dmd.105.008193

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Received for publication January 4, 2006.
Revised February 22, 2006.
Accepted for publication February 24, 2006.

Metabolism and Disposition of a Potent and Selective GABA-A{alpha}2/3 Receptor in Healthy Male Volunteers

Stacey L. Polsky-Fisher 1*, Stanley Vickers 1, Donghui Cui 2, Raju Subramanian 3, Byron H. Arison 1, Nancy G.B. Agrawal 1, Thanh V. Goel 1, Laura K. Vessey 1, M. Gail Murphy 1, Kenneth C. Lasseter 4, Richard C. Simpson 1, Jose M. Vega 3, A. David Rodrigues 2

1 Merck & Co., Inc. 2 Bristol-Myers Squibb 3 Amgen 4 Clinical Pharmacology Associates

* Address correspondence to: E-mail: stacey_polsky{at}merck.com

Abstract

[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 hr), exhibited an apparent terminal half-life of 6.7 hours, and accounted for approximately 53% of the total radioactivity in plasma. After seven 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. Additionally, 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, is metabolized extensively (t-butyl hydroxylation and N-deethylation > glucuronidation), and the metabolites are excreted in urine and feces.


Key words: excretion, HPLC, mass spectrometry, metabolite identification, pharmacokinetics, phase II drug metabolism, renal elimination


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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]


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