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Research ArticleArticle

BIOTRANSFORMATION OF A GABAA RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE N-CARBAMOYL METABOLITES

Christopher L. Shaffer, Mithat Gunduz, Thomas N. O'Connell, R. Scott Obach and Shiyin Yee
Drug Metabolism and Disposition November 2005, 33 (11) 1688-1699; DOI: https://doi.org/10.1124/dmd.105.004630
Christopher L. Shaffer
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Mithat Gunduz
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Thomas N. O'Connell
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R. Scott Obach
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Shiyin Yee
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Abstract

The absorption, metabolism, and excretion of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide monomethanesulfonate (1), a GABAA receptor partial agonist potentially useful in treating generalized anxiety disorder, have been evaluated in both Sprague-Dawley rats and cynomolgus monkeys using [14C]1. In both species, mass balance was achieved within 48 h postdose, with the majority of drug-related material excreted within the feces; the clearance of 1 in each species had both metabolic and renal components. In addition to the metabolites produced by aliphatic hydroxylation and/or N-dealkylation of 1, two unique metabolites were detected: a putative carbamic acid (M7) in rat plasma and monkey bile, and an N-carbamoyl glucuronide (M8) in both rat and monkey bile. Metabolite M8 was structurally deciphered by liquid chromatographytandem mass spectrometry and NMR, and was readily generated in vitro upon incubation of [14C]1 with rat liver microsomes fortified with uridine 5′-diphosphoglucuronic acid trisodium salt and alamethicin under a CO2 atmosphere. Treatment of M8 with β-glucuronidase afforded 1 directly. The presence of M8 in bile and its notable absence from other matrices suggests the enterohepatic cycling of 1 via M8. Although the structure of M7 was not elucidated unequivocally due to its inability to be formed in vitro and its minimal absolute quantities in limited biological matrices, data herein clearly support its structural rationalization. Furthermore, since M7 is the precursor of M8, detection of M8 is indirect evidence of its existence. It is proposed that M7 arises from an equilibrium between 1 and dissolved CO2-equivalents both in vivo and in vitro, similar to carbamino bonds observed in hemoglobin and certain amino acids, respectively.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.004630.

  • ABBREVIATIONS: GABAA, γ-aminobutyric acid type-A receptor; 1, N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide monomethanesulfonate; 2, 2-fluoro-4-[(4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-phenoxy acetic acid; 3, 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid [3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-amide; [14C]1, N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-[3-14C]indole-3-carboxamide monomethanesulfonate; SD, Sprague-Dawley; PGRD, Pfizer Global Research and Development; RLM, rat liver microsome; MLM, monkey liver microsome; HPLC, high-performance liquid chromatography; MeCN, acetonitrile; rcf, relative centrifugal force; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple-reaction monitoring; AUC, area under the plasma concentration-time curve; kel, elimination rate constant; NADPH, reduced β-nicotinamide adenine dinucleotide phosphate; LC, liquid chromatography; CID, collision-induced dissociation; UGT, uridine 5′-diphosphoglucuronic acid transferase; amu, atomic mass unit(s).

  • ↵1 Current address: TargeGen, San Diego, California.

    • Received March 7, 2005.
    • Accepted August 3, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (11)
Drug Metabolism and Disposition
Vol. 33, Issue 11
1 Nov 2005
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BIOTRANSFORMATION OF A GABAA RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE N-CARBAMOYL METABOLITES
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Research ArticleArticle

BIOTRANSFORMATION OF A GABAA RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE N-CARBAMOYL METABOLITES

Christopher L. Shaffer, Mithat Gunduz, Thomas N. O'Connell, R. Scott Obach and Shiyin Yee
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1688-1699; DOI: https://doi.org/10.1124/dmd.105.004630

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Research ArticleArticle

BIOTRANSFORMATION OF A GABAA RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE N-CARBAMOYL METABOLITES

Christopher L. Shaffer, Mithat Gunduz, Thomas N. O'Connell, R. Scott Obach and Shiyin Yee
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1688-1699; DOI: https://doi.org/10.1124/dmd.105.004630
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