RT Journal Article
SR Electronic
T1 In Vitro–In Vivo Inaccuracy: The CYP3A4 Anomaly
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1368
OP 1371
DO 10.1124/dmd.119.088427
VO 47
IS 12
A1 Christine M. Bowman
A1 Leslie Z. Benet
YR 2019
UL http://dmd.aspetjournals.org/content/47/12/1368.abstract
AB When predicting hepatic clearance using in vitro to in vivo extrapolation (IVIVE), microsomes or hepatocytes are commonly used. Here, we examine intrinsic clearance values and IVIVE results in human hepatocytes and microsomes for compounds metabolized by a variety of enzymes. The great majority of CYP3A4 substrates examined had higher intrinsic clearance values in microsomes compared with hepatocytes, whereas the values were more similar between the two incubations for substrates of other enzymes. We hypothesize that this may be due to interplay between CYP3A4 and the efflux transporter P-glycoprotein, as they have been shown to exhibit coordinated regulation. When examining the prediction accuracy for substrates of other enzymes between microsomes and hepatocytes, average fold errors as well as overall error were similar, demonstrating once again that IVIVE methods are not adequately defined and understood.SIGNIFICANCE STATEMENT For CYP3A4 substrates, microsomes give markedly higher predictive in vitro to in vivo extrapolation than for other metabolic enzymes, which is not found for hepatocytes. We hypothesize that this could be a result of CYP3A4–P-glycoprotein interplay or coordinated regulation in hepatocytes that would not be observed in microsomes.