Utility of Cryopreserved Hepatocytes Suspended in Serum to Predict Hepatic Clearance in Dogs and Monkeys

Yoshihiro Shibata, Jiro Kuze, Masato Chiba
2014 Drug Metabolism and Pharmacokinetics  
An in vitroin vivo correlation analysis between observed and predicted metabolic clearance in multiple preclinical species including dogs and monkeys constitutes an integral part of prediction for the pharmacokinetics in humans by using liver-derived in vitro preparations. Empirical values of the scaling factor for the extrapolation of metabolic (intrinsic) clearance in the in vitro preparation to that for whole liver were calculated for each preparation of 8 and 5 cryopreserved dog and monkey
more » ... epatocytes, respectively, by optimizing the objective function of average fold error between predicted and observed metabolic (intrinsic) clearance for eight and 11 standard compounds for dogs and monkeys, respectively. Thus obtained values of the scaling factor ranged from 5.46 © 10 9 to 19.9 © 10 9 cells/kg body weight with an average of 10.3 © 10 9 cells/kg body weight in dogs, and the value ranged from 2.36 © 10 9 to 4.21 © 10 9 cells/kg body weight with an average of 3.17 © 10 9 cells/kg body weight in monkeys, which were both consistent with biologically calculated values in corresponding species. These results demonstrated the utility of commercially available cryopreserved preparations of dog and monkey hepatocytes for the in vitroin vivo correlation analyses with the aid of empirically or biologically obtained scaling factors at the early development stage of new drug candidates.
doi:10.2133/dmpk.dmpk-13-rg-083 pmid:24042473 fatcat:iazuvq47lja2pkjjwfpe2cc7ha