Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV.
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 (approximately 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.
Walker
Don K
DK
Department of Pharmacokinetics, Dynamics and Metabolism (IPC 664), Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. don_walker@sandwich.pfizer.com
Abel
Samantha
S
Comby
Pierre
P
Muirhead
Gary J
GJ
Nedderman
Angus N R
AN
Smith
Dennis A
DA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D004311:Double-Blind Method; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D000077592:Maraviroc; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D001798:Blood Proteins; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc