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Research ArticleArticle

Pharmacokinetics and Differential Regulation of Cytochrome P450 Enzymes in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462
Tadatoshi Tanino
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Akira Komada
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Koji Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Toru Bando
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Yukie Nojiri
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Yukari Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Eiichi Sakurai
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Abstract

Type 1 allergic diseases are characterized by elevated production of specific immunoglobulin E (IgE) for each antigen and have become a significant health problem worldwide. This study investigated the effect of IgE-mediated allergy on drug pharmacokinetics. To further understand differential suppression of hepatic cytochrome P450 (P450) activity, we examined the inhibitory effect of nitric oxide (NO), a marker of allergic conditions. Seven days after primary sensitization (PS7) or secondary sensitization (SS7), hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities were decreased to 45%–75% of the corresponding control; however, CYP2D activity was not downregulated. PS7 and SS7 did not change the expression levels of five P450 proteins. Disappearance of CYP1A2 and CYP2D substrates from the plasma was not significantly different between allergic mice and control mice. In contrast, the area under the curve of a CYP1A2-mediated metabolite in PS7 and SS7 mice was reduced by 50% of control values. Total clearances of a CYP2E1 substrate in PS7 and SS7 mice were significantly decreased to 70% and 50% respectively, of the control without altering plasma protein binding. Hepatic amounts of CYP1A2 and CYP2E1 substrates were enhanced by allergic induction, being responsible for each downregulated activity. NO scavenger treatment completely improved the downregulated P450 activities. Therefore, our data suggest that the onset of IgE-mediated allergy alters the pharmacokinetics of major P450-metabolic capacity–limited drugs except for CYP2D drugs. NO is highly expected to participate in regulatory mechanisms of the four P450 isoforms.

Footnotes

    • Received July 11, 2016.
    • Accepted September 28, 2016.
  • The authors declare that there is no conflict of interest to disclose.

  • dx.doi.org/10.1124/dmd.116.072462.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Research ArticleArticle

Pharmacokinetics and P450 Inhibition in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462

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Research ArticleArticle

Pharmacokinetics and P450 Inhibition in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462
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