Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance.
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.
Novartis Institutes for Biomedical Research, Horsham, UK. rowan.stringer@novartis.com
R
R
Stringer
P L
PL
Nicklin
J B
JB
Houston
D001681:Biological Assay / Q000379:methods*; D002478:Cells, Cultured; D015925:Cryopreservation / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity