title: Establishment of In Silico Prediction Models for CYP3A4 and CYP2B6 Induction in Human Hepatocytes by Multiple Regression Analysis Using Azole Compounds.
abstract: Drug-drug interactions (DDIs) via cytochrome P450 (P450) induction are one clinical problem leading to increased risk of adverse effects and the need for dosage adjustments and additional therapeutic monitoring. In silico models for predicting P450 induction are useful for avoiding DDI risk. In this study, we have established regression models for CYP3A4 and CYP2B6 induction in human hepatocytes using several physicochemical parameters for a set of azole compounds with different P450 induction as characteristics as model compounds. To obtain a well-correlated regression model, the compounds for CYP3A4 or CYP2B6 induction were independently selected from the tested azole compounds using principal component analysis with fold-induction data. Both of the multiple linear regression models obtained for CYP3A4 and CYP2B6 induction are represented by different sets of physicochemical parameters. The adjusted coefficients of determination for these models were of 0.8 and 0.9, respectively. The fold-induction of the validation compounds, another set of 12 azole-containing compounds, were predicted within twofold limits for both CYP3A4 and CYP2B6. The concordance for the prediction of CYP3A4 induction was 87% with another validation set, 23 marketed drugs. However, the prediction of CYP2B6 induction tended to be overestimated for these marketed drugs. The regression models show that lipophilicity mostly contributes to CYP3A4 induction, whereas not only the lipophilicity but also the molecular polarity is important for CYP2B6 induction. Our regression models, especially that for CYP3A4 induction, might provide useful methods to avoid potent CYP3A4 or CYP2B6 inducers during the lead optimization stage without performing induction assays in human hepatocytes.
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical, Kyoto, Japan (M.N., Y.K., M.S.); Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (M.N., K.Y.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.) nagai_mika@kaken.co.jp.
authors.forename: Mika
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical, Kyoto, Japan (M.N., Y.K., M.S.); Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (M.N., K.Y.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Konno
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical, Kyoto, Japan (M.N., Y.K., M.S.); Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (M.N., K.Y.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.).
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satsukawa
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical, Kyoto, Japan (M.N., Y.K., M.S.); Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (M.N., K.Y.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.).
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical, Kyoto, Japan (M.N., Y.K., M.S.); Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (M.N., K.Y.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.).
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
mesh_terms: D000328:Adult; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D003198:Computer Simulation; D065702:Cytochrome P-450 CYP2B6 / Q000096:biosynthesis* / Q000235:genetics; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D065701:Cytochrome P-450 CYP3A Inducers / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015394:Molecular Structure; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D001393:Azoles; D065695:Cytochrome P-450 CYP2B6 Inducers; D065701:Cytochrome P-450 CYP3A Inducers; D012333:RNA, Messenger; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human