RT Journal Article
SR Electronic
T1 Preclinical Pharmacokinetics and Interspecies Scaling of a Novel Vitronectin Receptor Antagonist
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1232
OP 1241
VO 27
IS 11
A1 Keith W. Ward
A1 Leonard M. Azzarano
A1 William E. Bondinell
A1 Russell D. Cousins
A1 William F. Huffman
A1 Dalia R. Jakas
A1 Richard M. Keenan
A1 Thomas W. Ku
A1 Dave Lundberg
A1 William H. Miller
A1 Jayme A. Mumaw
A1 Kenneth A. Newlander
A1 Jill L. Pirhalla
A1 Theresa J. Roethke
A1 Kevin L. Salyers
A1 Pamela R. Souder
A1 Gary J. Stelman
A1 Brian R. Smith
YR 1999
UL http://dmd.aspetjournals.org/content/27/11/1232.abstract
AB 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 αvβ3 (“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 (r2< 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 (r2= 0.96). This study demonstrates a novel allometric correction that may be applicable to compounds that undergo conjugation and biliary excretion. The American Society for Pharmacology and Experimental Therapeutics