title: Preclinical pharmacokinetics and interspecies scaling of a novel vitronectin receptor antagonist.
abstract: Allometric scaling may be used in drug development to predict the pharmacokinetics of xenobiotics in humans from animal data. Although allometry may be successful for compounds that are excreted unchanged or that are oxidatively metabolized (with corrections for metabolic capacity), it has been more challenging for compounds excreted primarily as conjugates in bile. (S)-10, 11-Dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[ a, d]cycloheptene-10-acetic acid (SB-265123) is a novel alphavbeta3 ("vitronectin receptor") antagonist. In this study, the in vivo pharmacokinetics and in vitro plasma protein binding of SB-265123 were examined in four species: mice, rats, dogs, and monkeys. In monkeys and dogs, SB-265123 exhibited moderate clearance, whereas low clearance (<20% hepatic blood flow) was observed in the rat, and high clearance (>70% hepatic blood flow) was seen in the mouse. The concentration-time profiles indicated the possibility of enterohepatic recirculation; subsequent studies in bile duct-cannulated rats demonstrated extensive biliary excretion of an acyl-glucuronide of SB-265123. In allometric scaling to predict the disposition of SB-265123 in humans, various standard correction factors were applied, including protein binding, maximum lifespan potential, and brain weight; each failed to produce adequate interspecies scaling of clearance (r(2) < 0.72). Consequently, a novel correction factor incorporating bile flow and microsomal UDP-glucuronosyltransferase activity in each species was applied, demonstrating substantial improvement in the correlation of the allometric plot (r(2) = 0.96). This study demonstrates a novel allometric correction that may be applicable to compounds that undergo conjugation and biliary excretion.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals R&D, King of Prussia, Pennsylvania 19406, USA. Keith_W_Ward@sbphrd.com
authors.forename: K W
authors.initials: KW
authors.lastname: Ward
authors.forename: L M
authors.initials: LM
authors.lastname: Azzarano
authors.forename: W E
authors.initials: WE
authors.lastname: Bondinell
authors.forename: R D
authors.initials: RD
authors.lastname: Cousins
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
authors.forename: D R
authors.initials: DR
authors.lastname: Jakas
authors.forename: R M
authors.initials: RM
authors.lastname: Keenan
authors.forename: T W
authors.initials: TW
authors.lastname: Ku
authors.forename: D
authors.initials: D
authors.lastname: Lundberg
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: J A
authors.initials: JA
authors.lastname: Mumaw
authors.forename: K A
authors.initials: KA
authors.lastname: Newlander
authors.forename: J L
authors.initials: JL
authors.lastname: Pirhalla
authors.forename: T J
authors.initials: TJ
authors.lastname: Roethke
authors.forename: K L
authors.initials: KL
authors.lastname: Salyers
authors.forename: P R
authors.initials: PR
authors.lastname: Souder
authors.forename: G J
authors.initials: GJ
authors.lastname: Stelman
authors.forename: B R
authors.initials: BR
authors.lastname: Smith
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics*; D000631:Aminopyridines / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013045:Species Specificity
chemical_list: D000085:Acetates; D000631:Aminopyridines; D019030:Receptors, Vitronectin; C121647:SB 265123