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Research ArticleArticle

SPECIES DIFFERENCES IN THE DISPOSITION OF THE CCR5 ANTAGONIST, UK-427,857, A NEW POTENTIAL TREATMENT FOR HIV

Don K. Walker, Samantha Abel, Pierre Comby, Gary J. Muirhead, Angus N. R. Nedderman and Dennis A. Smith
Drug Metabolism and Disposition April 2005, 33 (4) 587-595; DOI: https://doi.org/10.1124/dmd.104.002626
Don K. Walker
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Samantha Abel
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Pierre Comby
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Gary J. Muirhead
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Angus N. R. Nedderman
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Dennis A. Smith
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Abstract

UK-427,857 (4, 4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D7.4 2.1) and basic (pKa 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (∼20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.

Footnotes

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

  • doi:10.1124/dmd.104.002626.

  • ABBREVIATIONS: HIV, human immunodeficiency virus; UK-427,857, 4, 4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide; DMSO, dimethyl sulfoxide; AUC, area under the curve; HPLC, high-performance liquid chromatography; A, apical; B, basolateral; P-gp, P-glycoprotein.

    • Received October 12, 2004.
    • Accepted January 12, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (4)
Drug Metabolism and Disposition
Vol. 33, Issue 4
1 Apr 2005
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Research ArticleArticle

SPECIES DIFFERENCES IN THE DISPOSITION OF THE CCR5 ANTAGONIST, UK-427,857, A NEW POTENTIAL TREATMENT FOR HIV

Don K. Walker, Samantha Abel, Pierre Comby, Gary J. Muirhead, Angus N. R. Nedderman and Dennis A. Smith
Drug Metabolism and Disposition April 1, 2005, 33 (4) 587-595; DOI: https://doi.org/10.1124/dmd.104.002626

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Research ArticleArticle

SPECIES DIFFERENCES IN THE DISPOSITION OF THE CCR5 ANTAGONIST, UK-427,857, A NEW POTENTIAL TREATMENT FOR HIV

Don K. Walker, Samantha Abel, Pierre Comby, Gary J. Muirhead, Angus N. R. Nedderman and Dennis A. Smith
Drug Metabolism and Disposition April 1, 2005, 33 (4) 587-595; DOI: https://doi.org/10.1124/dmd.104.002626
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