Abstract
The glycogen synthase kinase-3 inhibitor, LY2090314, specifically impaired cytochrome P450 (CYP) 2B6 activity during in vitro evaluation of CYP enzyme induction in human hepatocytes. CYP2B6 catalytic activity was significantly decreased following 3-day incubation with 0.1-10μM LY2090314, on average by 64.3±5.0% at 10μM. 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 ≤10μM, 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±0.043μM), which were significantly correlated with catalytic activity (r2 = 0.87, slope = 0.77; Imax = 57.0±10.8%, IC50 = 0.057±0.027μM). 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±1.2μM and 2.1±0.4μM, isoforms 1 and 3, respectively) and may be sufficiently extensive to overcome the weak but potent activation of PXR by ≤10μM LY2090314 (19.3±2.2% of maximal rifampin response, apparent EC50 = 1.2±1nM). The clinical relevance of these findings was evaluated through physiologically-based pharmacokinetic model simulations. CYP2B6 suppression by LY2090314 is not expected clinically, with 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 than LY2090314.
- CYP induction
- CYP inhibition
- CYP2B
- cytochrome P450 regulation
- drug interactions
- drug-drug interactions
- in vitro-in vivo prediction
- pharmacokinetic modeling
- physiologically-based modeling
- physiologically-based pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics