RT Journal Article
SR Electronic
T1 SPECIES DIFFERENCES IN THE DISPOSITION OF THE CCR5 ANTAGONIST, UK-427,857, A NEW POTENTIAL TREATMENT FOR HIV
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 587
OP 595
DO 10.1124/dmd.104.002626
VO 33
IS 4
A1 Don K. Walker
A1 Samantha Abel
A1 Pierre Comby
A1 Gary J. Muirhead
A1 Angus N. R. Nedderman
A1 Dennis A. Smith
YR 2005
UL http://dmd.aspetjournals.org/content/33/4/587.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics