TY - JOUR T1 - In Vitro–In Vivo Inaccuracy: The CYP3A4 Anomaly JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1368 LP - 1371 DO - 10.1124/dmd.119.088427 VL - 47 IS - 12 AU - Christine M. Bowman AU - Leslie Z. Benet Y1 - 2019/12/01 UR - http://dmd.aspetjournals.org/content/47/12/1368.abstract N2 - 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. ER -