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Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance.

Stringer, Rowan and Nicklin, Paul and Houston, J B (2008) Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance. Xenobiotica, 38 (10). pp. 1313-1329. ISSN 1366-5928

Abstract

A total of 110 drugs, selected to cover a range of physicochemical and pharmacokinetic properties, were used to explore standard approaches to the prediction of in vivo metabolic clearance using drug-depletion profiles from human liver microsomes (HLMs) and cyropreserved hepatocytes. A total of 41 drugs (37% of the compounds tested) showed measurable depletion rates using HLMs (depletion by 20% or more over the time course). The most reliable correlations in terms of bias (average fold error (AFE) = 2.32) and precision (root mean square error (RMSE) = 3501) were observed by comparing in vivo intrinsic clearance (CL(int)), calculated using the parallel-tube model and incorporating the fraction unbound in blood, with in vitro CL(int) adjusted for microsomal binding. For these reference drugs, 29% of predictions were within two-fold of the observed values and 66% were within five-fold. Compared with HLMs, clearance predictions with cryopreserved hepatocytes (57 drugs) were of similar precision (RMSE = 3608) but showed more bias (AFE = 5.21) with 18% of predictions within two-fold of the observed values and 46% within five-fold. However, with a broad complement of drug-metabolizing enzymes, hepatocytes catalysed measurable CL(int) values for a greater proportion (52%) of the reference compounds and were particularly proficient at defining metabolic rates for drugs with predominantly phase 2 metabolic routes.

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Date Deposited: 14 Dec 2009 13:49
Last Modified: 14 Dec 2009 13:49
URI: https://oak.novartis.com/id/eprint/1105

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