Investigational Small-Molecule Drug Selectively Suppresses Constitutive CYP2B6 Activity at the Gene Transcription Level: Physiologically Based Pharmacokinetic Model Assessment of Clinical Drug Interaction Risk

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 mu M LY2090314, on average by 64.3% +/- 5.0% at 10 mu M. 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 mM, 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 (I-max = 61.9% +/- 1.4%; IC50 = 0.049 +/- 0.043 mu M), which were significantly correlated with catalytic activity (r(2) = 0.87, slope = 0.77; I-max = 57.0% +/- 10.8%, IC50 = 0.057 +/- 0.027 mu M). 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 mu M for isoforms 1 and 3, respectively) and may be sufficiently extensive to overcome the weak but potent activation of pregnane X receptor by <= 10 mu M 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 co-administration. However, simulations showed that observed CYP2B6 suppression could be clinically relevant for a drug with different pharmacokinetic properties from LY2090314.