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OtherDRUG METABOLISM AND DISPOSITION

Oxidation of Histamine H1 Antagonist Mequitazine is Catalyzed by Cytochrome P450 2D6 in Human Liver Microsomes

Katsunori Nakamura, Tsuyoshi Yokoi, Takao Kodama, Kazuaki Inoue, Kazuo Nagashima, Noriaki Shimada, Toshiaki Shimizu and Tetsuya Kamataki
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 437-442;
Katsunori Nakamura
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Tsuyoshi Yokoi
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Takao Kodama
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Kazuaki Inoue
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Kazuo Nagashima
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Noriaki Shimada
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Toshiaki Shimizu
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Tetsuya Kamataki
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Abstract

Mequitazine [10-(3-quinuclidinylmethyl) phenothiazine] is a long-acting and selective histamine H1-receptor antagonist that is mainly biotransformed by human liver microsomes to yield hydroxylated and S-oxidized metabolites. Mequitazine hydroxylase was inhibited by propranolol and quinidine. Lineweaver-Burk plots for the hydroxylation and the S-oxidation indicated that the hydroxylation occurred with a low Km (0.72 ± .26 μM) in human liver microsomes. Microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochrome P450 2D6 (CYP2D6) efficiently metabolized mequitazine to the hydroxylated and S-oxidized metabolites. The results indicate that CYP2D6 isozyme is a major form of CYP responsible for the metabolism of mequitazine in human liver microsomes. Inhibition of CYP3A-catalyzed midazolam 1′-hydroxylase by various histamine H1 antagonists, including mequitazine, suggested that mequitazine and some other histamine H1 antagonists could also be inhibitors of CYP3A in human liver microsomes.

Footnotes

  • Send reprint requests to: Dr. Tetsuya Kamataki, Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, N12W6, Sapporo 060 Japan.

  • 1 This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.

  • Abbreviations:
    CYP
    cytochrome P450
    FMO
    flavin-containing monooxygenase
    HPLC
    high-performance liquid chromatography
    PM
    poor metabolizer
    EM
    extensive metabolizer
    • Received June 13, 1997.
    • Accepted October 6, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherDRUG METABOLISM AND DISPOSITION

Oxidation of Histamine H1 Antagonist Mequitazine is Catalyzed by Cytochrome P450 2D6 in Human Liver Microsomes

Katsunori Nakamura, Tsuyoshi Yokoi, Takao Kodama, Kazuaki Inoue, Kazuo Nagashima, Noriaki Shimada, Toshiaki Shimizu and Tetsuya Kamataki
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 437-442;

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OtherDRUG METABOLISM AND DISPOSITION

Oxidation of Histamine H1 Antagonist Mequitazine is Catalyzed by Cytochrome P450 2D6 in Human Liver Microsomes

Katsunori Nakamura, Tsuyoshi Yokoi, Takao Kodama, Kazuaki Inoue, Kazuo Nagashima, Noriaki Shimada, Toshiaki Shimizu and Tetsuya Kamataki
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 437-442;
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