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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.104.002626v1 33/4/587    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 Walker, D. K. Articles by Smith, D. A. Search for Related Content PubMed PubMed Citation Articles by Walker, D. K. Articles by Smith, D. A.

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

Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (D.K.W., A.N.R.N., D.A.S.); Department of Clinical Pharmacology, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (S.A., G.J.M.); and Department of Safety Sciences, Pfizer Global Research and Development, Amboise Cedex, France (P.C.)

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 D_7.4 2.1) and basic (pK_a 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.

This article has been cited by other articles:

				J.-P. H. T. M. Ploemen, H. Kramer, E. I. Krajnc, and I. Martin The Use of Toxicokinetic Data in Preclinical Safety Assessment: A Toxicologic Pathologist Perspective Toxicol Pathol, October 1, 2007; 35(6): 834 - 837. [Abstract] [Full Text] [PDF]

				S. Aquaro, V. Svicher, D. Schols, M. Pollicita, A. Antinori, J. Balzarini, and C. F. Perno Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies J. Leukoc. Biol., November 1, 2006; 80(5): 1103 - 1110. [Abstract] [Full Text] [PDF]

				S. M. Gardiner, J. E. March, P. A. Kemp, S. A. Ballard, and T. Bennett Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT1) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 340 - 348. [Abstract] [Full Text] [PDF]