1998 Fiscal Year Final Research Report Summary
Role of intestinal oxidative metabolism on first pass effect
| Project/Area Number |
09470496
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
YAMAZOE Yasushi Tohoku Univ., Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00112699)
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| 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)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Drug metabolism / Drug interaction / Grapefruit juice / Gut / CYP3A / Omeprazole |
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| 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.
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