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Research ArticleArticle

Furanocoumarin Derivatives in Kampo Extract Medicines Inhibit Cytochrome P450 3A4 and P-Glycoprotein

Kazunori Iwanaga, Manami Hayashi, Yukimi Hamahata, Makoto Miyazaki, Makio Shibano, Masahiko Taniguchi, Kimiye Baba and Masawo Kakemi
Drug Metabolism and Disposition August 2010, 38 (8) 1286-1294; DOI: https://doi.org/10.1124/dmd.110.032847
Kazunori Iwanaga
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Manami Hayashi
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Yukimi Hamahata
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Makoto Miyazaki
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Makio Shibano
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Masahiko Taniguchi
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Kimiye Baba
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Masawo Kakemi
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Abstract

Furanocoumarins in grapefruit are known to show inhibitory effects against P-glycoprotein (P-gp) and CYP3A4 in intestinal epithelial cells; however, furanocoumarin derivatives are widely contained in the plants of Rutaceae and Umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of 12 furanocoumarins extracted from plants in the Umbelliferae family against P-gp and CYP3A4 activity. Furthermore, we studied their inhibitory effect on P-gp when furanocoumarins are used as Kampo extract medicine rather than as an isolated single compound. From screening of the CYP3A4 inhibitory effect, notopterol and rivulobirin A, the only dimer types of furanocoumarin, were found to be potent inhibitors of CYP3A4. On the other hand, byakangelicol and rivulobirin A showed strong P-gp inhibition from the screening of P-gp inhibitor evaluated by quinidine permeation through the Caco-2 monolayer; however, the chemical structural relationship of furanocoumarins between P-gp and CYP3A4 inhibitory effects could not be obtained. We also investigated the effect of these furanocoumarins on the transport of digoxin through the Caco-2 monolayer. The inhibitory effect of rivulobirin A was more potent than that of byakangelicol. Application of either Senkyu-cha-cho-san or Sokei-kakketsu-to, which are composed of herbal remedies in the Umbelliferae group, significantly decreased the efflux ratio of digoxin. In conclusion, it was found that some furanocoumarins extracted from the plants in the Umbelliferae family strongly inhibited P-gp and CYP3A4. Kampo extract medicines containing herbal remedies belonging to the Umbelliferae family may cause a drug-drug interaction with P-gp or a CYP3A4 substrate drug.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032847.

  • ABBREVIATIONS:

    P-gp
    P-glycoprotein
    DDI
    drug-drug interaction
    LC
    liquid chromatography
    MS
    mass spectrometry
    OH
    hydroxy
    HPLC
    high-performance liquid chromatography
    FC726
    4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl-2-octenyl] oxy]-7H-furo[3,2-g][1]benzopyran-7-one
    MBI
    mechanism-based inhibition
    OATP/oatp
    organic anion-transporting polypeptide
    GF120918
    N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide.

  • Received February 15, 2010.
  • Accepted May 12, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Research ArticleArticle

Furanocoumarin Derivatives in Kampo Extract Medicines Inhibit Cytochrome P450 3A4 and P-Glycoprotein

Kazunori Iwanaga, Manami Hayashi, Yukimi Hamahata, Makoto Miyazaki, Makio Shibano, Masahiko Taniguchi, Kimiye Baba and Masawo Kakemi
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1286-1294; DOI: https://doi.org/10.1124/dmd.110.032847

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Research ArticleArticle

Furanocoumarin Derivatives in Kampo Extract Medicines Inhibit Cytochrome P450 3A4 and P-Glycoprotein

Kazunori Iwanaga, Manami Hayashi, Yukimi Hamahata, Makoto Miyazaki, Makio Shibano, Masahiko Taniguchi, Kimiye Baba and Masawo Kakemi
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1286-1294; DOI: https://doi.org/10.1124/dmd.110.032847
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