PT - JOURNAL ARTICLE AU - Dermot F. McGinnity AU - Matthew G. Soars AU - Richard A. Urbanowicz AU - Robert J. Riley TI - EVALUATION OF FRESH AND CRYOPRESERVED HEPATOCYTES AS IN VITRO DRUG METABOLISM TOOLS FOR THE PREDICTION OF METABOLIC CLEARANCE AID - 10.1124/dmd.104.000026 DP - 2004 Nov 01 TA - Drug Metabolism and Disposition PG - 1247--1253 VI - 32 IP - 11 4099 - http://dmd.aspetjournals.org/content/32/11/1247.short 4100 - http://dmd.aspetjournals.org/content/32/11/1247.full SO - Drug Metab Dispos2004 Nov 01; 32 AB - The intrinsic clearances (CLint) of 50 neutral and basic marketed drugs were determined in fresh human hepatocytes and the data used to predict human in vivo hepatic metabolic clearance (CLmet). A statistically significant correlation between scaled CLmet and actual CLmet was observed (r2 = 0.48, p < 0.05), and for 73% of the drugs studied, scaled clearances were within 2-fold of the actual clearance. These data have shown that CLint data generated in human hepatocytes can be used to provide estimates of human hepatic CLmet for both phase I and phase II processes. In addition, the utility of commercial and in-house cryopreserved hepatocytes was assessed by comparing with data derived from fresh cells. A set of 14 drugs metabolized by the major human cytochromes P450 (P450s) (CYP1A2, 2C9, 2C19, 2D6, and 3A4) and uridine diphosphate glucuronosyltransferases (UGT1A1, 1A4, 1A9, and 2B7) have been used to characterize the activity of freshly isolated and cryopreserved human and dog hepatocytes. The cryopreserved human and dog cells retained on average 94% and 81%, respectively, of the CLint determined in fresh cells. Cryopreserved hepatocytes retain their full activity for more than 1 year in liquid N2 and are thus a flexible resource of hepatocytes for in vitro assays. In summary, this laboratory has successfully cryopreserved human and dog hepatocytes as assessed by the turnover of prototypic P450 and UGT substrates, and both fresh and cryopreserved human hepatocytes may be used for the prediction of human hepatic CLmet. The American Society for Pharmacology and Experimental Therapeutics