RT Journal Article
SR Electronic
T1 Use of Hepatocytes to Assess the Contribution of Hepatic Uptake to Clearance in Vivo
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 859
OP 865
DO 10.1124/dmd.106.014464
VO 35
IS 6
A1 Soars, Matthew G.
A1 Grime, Ken
A1 Sproston, Joanne L.
A1 Webborn, Peter J. H.
A1 Riley, Robert J.
YR 2007
UL http://dmd.aspetjournals.org/content/35/6/859.abstract
AB The wealth of information that has emerged in recent years detailing the substrate specificity of hepatic transporters necessitates an investigation into their potential role in drug elimination. Therefore, an assay in which the loss of parent compound from the incubation medium into hepatocytes (“media loss” assay) was developed to assess the impact of hepatic uptake on unbound drug intrinsic clearance in vivo (CLint ub in vivo). Studies using conventional hepatocyte incubations for a subset of 36 AstraZeneca new chemical entities (NCEs) resulted in a poor projection of CLint ub in vivo (r2 = 0.25, p = 0.002, average fold error = 57). This significant underestimation of CLint ub in vivo suggested that metabolism was not the dominant clearance mechanism for the majority of compounds examined. However, CLint ub in vivo was described well for this dataset using an initial compound “disappearance” CLint obtained from media loss assays (r2 = 0.72, p = 6.3 × 10-11, average fold error = 3). Subsequent studies, using this method for the same 36 NCEs, suggested that the active uptake into human hepatocytes was generally slower (3-fold on average) than that observed with rat hepatocytes. The accurate prediction of human CLint ub in vivo (within 4-fold) for the marketed drug transporter substrates montelukast, bosentan, atorvastatin, and pravastatin confirmed further the utility of this assay. This work has described a simple method, amenable for use within a drug discovery setting, for predicting the in vivo clearance of drugs with significant hepatic uptake. The American Society for Pharmacology and Experimental Therapeutics