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Research ArticleArticle

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

Maciej J. Zamek-Gliszczynski, Michael A. Mohutsky, Jessica L. F. Rehmel and Alice B. Ke
Drug Metabolism and Disposition June 2014, 42 (6) 1008-1015; DOI: https://doi.org/10.1124/dmd.114.057018
Maciej J. Zamek-Gliszczynski
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Michael A. Mohutsky
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Jessica L. F. Rehmel
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Alice B. Ke
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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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 (r2 = 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.

Footnotes

    • Received January 13, 2014.
    • Accepted March 19, 2014.
  • dx.doi.org/10.1124/dmd.114.057018.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (6)
Drug Metabolism and Disposition
Vol. 42, Issue 6
1 Jun 2014
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Research ArticleArticle

Xenobiotic Selectively Suppresses CYP2B6

Maciej J. Zamek-Gliszczynski, Michael A. Mohutsky, Jessica L. F. Rehmel and Alice B. Ke
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1008-1015; DOI: https://doi.org/10.1124/dmd.114.057018

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Research ArticleArticle

Xenobiotic Selectively Suppresses CYP2B6

Maciej J. Zamek-Gliszczynski, Michael A. Mohutsky, Jessica L. F. Rehmel and Alice B. Ke
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1008-1015; DOI: https://doi.org/10.1124/dmd.114.057018
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