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1998 Fiscal Year Final Research Report Summary

Role of intestinal oxidative metabolism on first pass effect

Research Project

Project/Area Number 09470496
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionTohoku University

Principal Investigator

YAMAZOE Yasushi  Tohoku Univ., Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00112699)

Co-Investigator(Kenkyū-buntansha) YOSHIDA Makoto  Tohoku Univ., Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (90201011)
NAGATA Kiyoshi  Tohoku Univ., Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80189133)
Project Period (FY) 1997 – 1998
KeywordsDrug metabolism / Drug interaction / Grapefruit juice / Gut / CYP3A / Omeprazole
Research Abstract

In rabbit Intestine, the expression of CYP1A, CYP2C, CYP2D and CYP3A proteins was detected by immuno blot analyses, and CYP3A forms were found to be induced by rifampicin.
Five components were isolated from grapefruit juice that inhibit human CYP3A-mediated drug oxidation. They include two furocoumarin dimers (GF-I-1 and GF-I-4) which are strong candi-dates for causative agents of grapefruit juice-mediated drug interaction.
Addition of ethyl acetate extract of grapefruit juice Into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, CYP2C19 and CYP2D6. The furocoumarins clearly Inhibited CYP3A4-catalyzed nifedipine oxidation in dose- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furocoumarin investigated, furocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4.
To determine the effect of grapefruit juice on omeprazole metabolism in vivo, omeprazole was taken orally by 13 healthy volunteers. AUC ratio of omeprazole sulfone to omeprazole, index of CYP3A4 activity, was decreased 33% (p< 0.001) by grapefruit juice intake whereas AUC ratio of 5-hydroxyomeprazole to omeprazole, index of liver-specific expressed CYP2C 19 activity, did not differ between two experiments. These data suggest that effect of grapefruit juice may confine within gastrointestinal tract, and not extend to hepatic P450s.

  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] K.Fukuda: "Grapefruit component interacting with rat and human P450 CYP3A : possible involvement of non-flavonoid components in drug interaction" Biol.Pharm.Bull.20. 560-564 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Fukuda: "Specific CYP3A4 inhibitors in grapefruit juice : furocoumarin dimers as components of drug interaction" Pharmacogenetics. 7. 391-396 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 山添 康: "グレープフルーツジュースと薬物相互作用" 日薬理誌. 113. 279- (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 山添 康: "薬物相互作用" 現代医学の基礎. 13. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Fukuda: "Grapefruitcomponent interacting with rat and human P450 CYP3A : possible involvement of non-flavonoid component in drug interac tion" Biol.Pharm.Bull.20. 560-564 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Fukuda: "Specific CYP3A4 inhibitors in grapefruit juice : furocoumarin dimers as components of drug interaction" Parmacogenetics. 7. 391-396 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 113. 279 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 13. (1999)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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