PT  - JOURNAL ARTICLE
AU  - Liyue Huang
AU  - Loren Berry
AU  - Sindhura Ganga
AU  - Brett Janosky
AU  - April Chen
AU  - Jonathan Roberts
AU  - Adria E. Colletti
AU  - Min-Hwa Jasmine Lin
TI  - Relationship between Passive Permeability, Efflux, and Predictability of Clearance from In Vitro Metabolic Intrinsic Clearance
AID  - 10.1124/dmd.109.029066
DP  - 2010 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 223--231
VI  - 38
IP  - 2
4099  - http://dmd.aspetjournals.org/content/38/2/223.short
4100  - http://dmd.aspetjournals.org/content/38/2/223.full
SO  - Drug Metab Dispos2010 Feb 01; 38
AB  - In vitro intrinsic metabolic clearance (CLint) is used routinely for compound selection in drug discovery; however, in vitro CLint often underpredicts in vivo clearance (CL). Forty-one proprietary compounds and 16 marketed drugs were selected to determine whether permeability and efflux status could influence the predictability of CL from in vitro CLint obtained from liver microsomal and hepatocyte incubations. For many of the proprietary compounds examined, rat CL was significantly underpredicted using the well stirred model incorporating both fraction of unbound drug in blood and fraction of unbound drug in the microsomal or hepatocyte incubation. Further analysis revealed that the accuracy of the prediction was differentiated by permeability and P-glycoprotein- (P-gp) and mouse breast cancer resistance protein (mBcrp)-mediated efflux. For proprietary compounds with passive permeability greater than 5 × 10−6 cm/s and efflux ratios less than 5 in both P-gp- and mBcrp-expressing cells, CLint provided reasonable prediction. The average -fold error (AFE) was 1.8 for rat liver microsomes (RLMs) and 2.3 for rat hepatocytes. In contrast, CL was dramatically underpredicted for compounds with passive permeability less than 5 × 10−6 cm/s; AFEs of 54.4 and 29.2 were observed for RLM and rat hepatocytes, respectively. In vivo CL was also underpredicted for compounds that were good efflux substrates (permeability >5 × 10−6 cm/s). The AFEs were 7.4 and 8.1 for RLM and rat hepatocytes, respectively. A similar relationship between permeability, efflux status, and human CL prediction reported in the literature was observed for 16 marketed drugs. These data show that permeability and efflux status are determinants for the predictability of CL from in vitro metabolic CLint. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics