Relationship between passive permeability, efflux, and predictability of clearance from in vitro metabolic intrinsic clearance.
In vitro intrinsic metabolic clearance (CL(int)) is used routinely for compound selection in drug discovery; however, in vitro CL(int) 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 CL(int) 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 x 10(-6) cm/s and efflux ratios less than 5 in both P-gp- and mBcrp-expressing cells, CL(int) 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 x 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 x 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 CL(int).
Huang
Liyue
L
Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA. liyueh@amgen.com
Berry
Loren
L
Ganga
Sindhura
S
Janosky
Brett
B
Chen
April
A
Roberts
Jonathan
J
Colletti
Adria E
AE
Lin
Min-Hwa Jasmine
MH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D004285:Dogs; D019450:Genes, MDR; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D034421:Sus scrofa
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D004364:Pharmaceutical Preparations