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

Xenobiotica. 2008 Oct;38(10):1313-29. doi: 10.1080/00498250802446286.


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.

MeSH terms

  • Biological Assay / methods*
  • Cells, Cultured
  • Cryopreservation / methods*
  • Hepatocytes / metabolism*
  • Humans
  • Metabolic Clearance Rate
  • Microsomes, Liver / metabolism*
  • Pharmacokinetics*
  • Reproducibility of Results
  • Sensitivity and Specificity