title: Development of a Specific Substrate-Inhibitor Panel (Liver-on-a-Chip) for Evaluation of Cytochrome P450 Activity.
abstract: We developed a cytochrome P450 substrate-inhibitor panel for preclinical in vitro evaluation of drugs in a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). The concentrations of substrates and inhibitors were optimized to ensure reliable detection of the principal metabolites by HPLC-mass-spectroscopy. The selected specific substrate-inhibitor pairs, namely bupropion/2-phenyl-2-(1-piperidinyl)propane) for evaluation of CYP2B6B activity, tolbutamide/sulfaphenazole for CYP2C9, omeprazole/(+)-N-benzylnirvanol for CYP2C19, and testosterone/ketoconazole for CYP3A4, enable reliable evaluation of the drug metabolism pathway. In contrast to animal models characterized by species-specific expression profile and activity of cytochrome P450 isoforms, our in vitro model reflects the metabolism of human hepatocytes in vivo.
authors.affiliation: Biocilicum Research and Production Center, Moscow, Russia. zakhariants@bioclinicum.com.
authors.forename: A A
authors.initials: AA
authors.lastname: Zakhariants
authors.affiliation: Biocilicum Research and Production Center, Moscow, Russia.
authors.forename: O A
authors.initials: OA
authors.lastname: Burmistrova
authors.affiliation: P. A. Hertsen Moscow Oncology Research Institute, Moscow, Russia.
authors.forename: M Y
authors.initials: MY
authors.lastname: Shkurnikov
authors.affiliation: Biocilicum Research and Production Center, Moscow, Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Poloznikov
authors.affiliation: Biocilicum Research and Production Center, Moscow, Russia.
authors.forename: D A
authors.initials: DA
authors.lastname: Sakharov
mesh_terms: D016642:Bupropion / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065702:Cytochrome P-450 CYP2B6 / Q000032:analysis / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000032:analysis / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000032:analysis / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000032:analysis / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D056656:Lab-On-A-Chip Devices; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D013058:Mass Spectrometry; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009853:Omeprazole / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013379:Substrate Specificity; D013426:Sulfaphenazole / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism; D014044:Tolbutamide / Q000378:metabolism
chemical_list: C412835:2-phenyl-2-(1-piperidinyl)propane; D065607:Cytochrome P-450 Enzyme Inhibitors; C454675:N-3-benzylnirvanol; D016642:Bupropion; D013426:Sulfaphenazole; D013739:Testosterone; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010622:Phencyclidine; D009853:Omeprazole; D008617:Mephenytoin; D007654:Ketoconazole
keywords: HepaRG; biotransformation; liver cell model; liver-on-a-chip; preclinical in vitro studies