Preclinical pharmacokinetics and interspecies scaling of a novel vitronectin receptor antagonist

Allometric scaling may be used in drug development to predict the pharmacok inetics of xenobiotics in humans from animal data. Although allometry may b e successful for compounds that are excreted unchanged or that are oxidativ ely 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]cyclohepte ne-10-acetic acid (SB-265123) is a novel alpha v beta 3 ("vitronectin recep tor") antagonist. In this study, the in vivo pharmacokinetics and in vitro plasma protein binding of SB-265123 were examined in four species: mice, ra ts, dogs, and monkeys. In monkeys and dogs, SB-265123 exhibited moderate cl earance, whereas low clearance (<20% hepatic blood flow) was observed in th e 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 allome tric scaling to predict the disposition of SB-265123 in humans, various sta ndard correction factors were applied, including protein binding, maximum l ifespan potential, and brain weight; each failed to produce adequate inters pecies 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 demons trates a novel allometric correction that may be applicable to compounds th at undergo conjugation and biliary excretion.