開心術後 Warfarin と PPI の相互作用による合併症回避のためのリスクマネージメントを目標としたゲノム解析  [in Japanese] Genomic Analysis for Preventing Complications due to Proton Pump Inhibitor and Warfarin Combination Therapy after Open-Heart Surgery  [in Japanese]

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Author(s)

    • 木村 玄 Kimura Haruka
    • 日本大学大学院医学研究科循環器外科学 Division of Cardiovascular Surgery, Department of Surgery, Postgraduate School of Nihon University
    • 秦 光賢 Hata Mitsumasa
    • 日本大学大学院医学研究科循環器外科学 Division of Cardiovascular Surgery, Department of Surgery, Postgraduate School of Nihon University
    • 塩野 元美 Shiono Motomi
    • 日本大学大学院医学研究科循環器外科学 Division of Cardiovascular Surgery, Department of Surgery, Postgraduate School of Nihon University

Abstract

[背景・目的]開心術後早期のプロトンポンプ阻害薬(PPI)の投与は,ストレス性消化管合併症の予防に有効であるが,PPIは抗凝固療法として用いるワルファリン(WF)と併用した場合,チトクロームP-450(CYP)2C19による代謝過程を共有するため,INR(International Normalizing Ratio)が急上昇し出血合併症のリスクとなる.[対象]CYP2C19の遺伝子亜型は代謝の早いEM(Extensive Metabolizer)型,遅いPM(Poor Metabolizer)型,中間のIM(Intermediate Metabolizer)型の3種が存在するが,WF,PPIの競合作用における遺伝子の関与については不明である.[結果]われわれは,PPIの種類とCYP2C19遺伝子亜型による薬剤相互作用への影響に関して研究を行った.PPIはその種類によってOmeprazole,Lansoprazole,Rabeprazoleの順にCYP2C19に対する代謝依存度が強く,Rabeprazoleにおいては主に非酵素的に代謝される.日本人では5人に1人がCYP2C19におけるPMであるとされ,他民族に比べ出血合併症をきたしやすいといわれている.今回,開心術後のWarfarinとPPIの併用について,前向き観察研究にてその競合作用とCYP2C19の遺伝子型について検討を行った.78例の患者から遺伝子解析を行い,VKORC1(Vitamin K epoxide reductase complex subunit 1)遺伝子型がT/T変異,CYP2C9遺伝子型が <sup>*</sup>1/<sup>*</sup>1で統一されたRabeprazole内服群(RB群)30例,Lansoprazole内服群(LP群)30例で比較検討を行った.[結果]Lansoprazole+Warfarin併用症例では,TTR(Time in Therapeutic Range)の低下が有意に見られ,その原因として有意差はなかったもののCYP2C19遺伝子型が関与している可能性が考えられた.また出血リスクとして年齢があげられたことより,とくに今後高齢化社会においては,Warfarinと併用するPPIとしてRabeprazoleが最も安全で有効であると考えられた.

<b>Objective</b> : Prevention of gastrointestinal bleeding is imperative in perioperative management of open-heart surgery. Although both proton pump inhibitors (PPIs) and Warfarin are often prescribed to patients following cardiac surgery, the US FDA warns that PPIs increase the international normalized ratio (INR) when used concomitantly with Warfarin, by being metabolized by cytochrome P-450 (CYP) 2C19. We assessed whether this drug interaction depends on the genotype of CYP2C19 (Extensive Metabolizer, EM ; Intermediate Metabolizer, IM ; Poor Metabolizer, PM) or the type of PPI. <b>Methods and Results</b> : In this observational prospective study, the CYP2C9, CYP2C19, and VKORC1 genotypes of 78 patients were analyzed. After excluding cases with <sup>*</sup>1/<sup>*</sup>3 of the CYP2C9 genotype and those with C/T of the VKORC1 genotype, 60 patients were assigned to Warfarin+Rabeprazole (RB group, 30 cases) or Warfarin+Lansoprazole (LP group, 30 cases). Warfarin was started with an initial dose of 3 mg, and INR values were measured on days 4, 8, 14, 28, and 56. There was no significant difference in median Warfarin dose between the LP group (2.5 mg/day) and RB group (3.0 mg/day), (<i>p</i>=0.88). The time in the therapeutic range (TTR) (Rosendaal) was significantly higher in the RB group (83.7%) than in the LP group (49.4%), and the time in the over range was significantly higher in the LP group (41.9%) than in the RB group (0.0%). In the LP group, TTR values were higher in CYP2C19 Extensive Metabolizers (EMs) than in Intermediate Metabolizers (IMs) and Poor Metabolizers (PMs), but there was no statistically significant difference between them. Conversely, in the RB group, there was no difference in the values of any CYP2C19 genotype. A multivariate analysis showed that high age and low TTR were risk factors for bleeding. <b>Conclusion</b> : We consider it possible that lower TTR values in the LP group were affected by the CYP2C19 genotype. In an aging society, Rabeprazole is safer and more effective as a proton pump inhibitor after open-heart surgery.

Journal

  • Japanese Journal of Cardiovascular Surgery

    Japanese Journal of Cardiovascular Surgery 43(4), 163-169, 2014

    The Japanese Society for Cardiovascular Surgery

Codes

  • NII Article ID (NAID)
    130004679591
  • Text Lang
    JPN
  • ISSN
    0285-1474
  • Data Source
    J-STAGE 
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