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Received for publication March 30, 2004.
Revised June 18, 2004.
Accepted for publication July 30, 2004.
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 were assessed by comparing with data derived from fresh cells. A set of 14 drugs metabolised by the major human cytochrome P450s (CYP1A2, 2C9, 2C19, 2D6, and 3A4) and uridine diphosphate glucuronosyltransferases (UGT1A1, 1A4, 1A9 and 2B7) have been used to characterise the activity of freshly isolated and cryopreserved human and dog hepatocytes. The cryopreserved human and dog cells retained on average 94 % and 81 % of the Clint determined in fresh cells, respectively. Cryopreserved hepatocytes retain their full activity for more than one 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 CYP and UGT substrates and both fresh and cryopreserved human hepatocytes may be used for the prediction of human hepatic Clmet.
Key words:
cytochrome P450, cytochrome P450 catalyzed oxidations, drug clearance, glucuronidation, hepatic elimination, hepatocytes, human pharmacokinetics, in vitro-in vivo prediction, in vitro-in vivo scaling, isolated hepatocytes
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