| Project/Area Number |
18K15393
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | Nagasaki University |
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Principal Investigator |
ISHII Koji 長崎大学, 病院(医学系), 助教 (40404248)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | ワルファリン / 光学異性体 / オピオイド / 相互作用 / 緩和医療 |
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| Outline of Final Research Achievements |
The present study was undertaken to examine whether in vivo vitamin K epoxide reductase complex 1 (VKOR) “actual” antagonism activity, calculated by the concentrations and the reported anticoagulant activities of the R- and S-warfarin enantiomers and their metabolites, correlates with the weekly dose of warfarin. Five patients under palliative care were enrolled in our study and 20 serum samples were analyzed by an enantioselective high-performance liquid chromatography ultraviolet detection method. In vivo VKOR inhibition activities of S-warfarin, R-warfarin, 7- and 10-hydroxywarfarin were calculated as the ratio of drug or metabolite concentration to the IC50. The mean drug concentrations (± SD) of S- and R-warfarin, 7-hydroxywarfarin and 10-hydroxywarfarin were 334 ± 154 ng/ml, 370 ± 115 ng/ml, 42 ± 15 ng/ml and 80 ± 44 ng/ml, respectively. Good correlation (R2 = 0.69-0.72) was obtained between the weekly warfarin dose and the ratios of INR/ actual antagonism activity.
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| Academic Significance and Societal Importance of the Research Achievements |
抗凝固作用をもつワルファリンは医療上広く使われている。しかし、ワルファリンの効果の強さは個人差が大きく、これまで遺伝子による予測などが試みられてきたが、有効との判断はなされていない。本研究では、鎮痛薬を多用する緩和医療を受けている患者のワルファリンの体内寿命（体内から出ていくまでの過程や速さ）が通常と異なることを見出した。また、ワルファリンと体内で変化した代謝物を個別に測定し、測定値とそれぞれの活性値を掛け合わせた実活性がワルファリンの投与量と相関することを明らかにした。以上の結果は、ワルファリンの適正使用に大きく貢献するものと期待される。
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