title: Investigational small-molecule drug selectively suppresses constitutive CYP2B6 activity at the gene transcription level: physiologically based pharmacokinetic model assessment of clinical drug interaction risk.
abstract: The glycogen synthase kinase-3 inhibitor LY2090314 specifically impaired CYP2B6 activity during in vitro evaluation of cytochrome P450 (P450) enzyme induction in human hepatocytes. CYP2B6 catalytic activity was significantly decreased following 3-day incubation with 0.1-10 μM LY2090314, on average by 64.3% ± 5.0% at 10 μM. These levels of LY2090314 exposure were not cytotoxic to hepatocytes and did not reduce CYP1A2 and CYP3A activities. LY2090314 was not a time-dependent CYP2B6 inhibitor, did not otherwise inhibit enzyme activity at concentrations ≤10 μM, and was not metabolized by CYP2B6. Thus, mechanism-based inactivation or other direct interaction with the enzyme could not explain the observed reduction in CYP2B6 activity. Instead, LY2090314 significantly reduced CYP2B6 mRNA levels (Imax = 61.9% ± 1.4%; IC50 = 0.049 ± 0.043 μM), which were significantly correlated with catalytic activity (r(2) = 0.87, slope = 0.77; Imax = 57.0% ± 10.8%, IC50 = 0.057 ± 0.027 μM). Direct inhibition of constitutive androstane receptor by LY2090314 is conceptually consistent with the observed CYP2B6 transcriptional suppression (Imax = 100.0% ± 10.8% and 57.1% ± 2.4%; IC50 = 2.5 ± 1.2 and 2.1 ± 0.4 μM for isoforms 1 and 3, respectively) and may be sufficiently extensive to overcome the weak but potent activation of pregnane X receptor by ≤10 μM LY2090314 (19.3% ± 2.2% of maximal rifampin response, apparent EC50 = 1.2 ± 1.1 nM). The clinical relevance of these findings was evaluated through physiologically based pharmacokinetic model simulations. CYP2B6 suppression by LY2090314 is not expected clinically, with a projected <1% decrease in hepatic enzyme activity and <1% decrease in hydroxybupropion exposure following bupropion coadministration. However, simulations showed that observed CYP2B6 suppression could be clinically relevant for a drug with different pharmacokinetic properties from LY2090314.
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mohutsky
authors.forename: Jessica L F
authors.initials: JL
authors.lastname: Rehmel
authors.forename: Alice B
authors.initials: AB
authors.lastname: Ke
mesh_terms: D016642:Bupropion / Q000494:pharmacology; D045744:Cell Line, Tumor; D065702:Cytochrome P-450 CYP2B6 / Q000096:biosynthesis* / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology*
chemical_list: C584053:3-(9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro(1,4)diazepino(6,7,1-hi)indol-7-yl)-4-imidazo(1,2-a)pyridin-3-yl-1H-pyrrole-2,5-dione; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015507:Drugs, Investigational; D006575:Heterocyclic Compounds, 3-Ring; D008301:Maleimides; D016642:Bupropion; D065702:Cytochrome P-450 CYP2B6