Journal of Thrombosis and Thrombolysis

, Volume 43, Issue 3, pp 333–342 | Cite as

Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel

  • Takahisa Furuta
  • Mitsushige Sugimoto
  • Chise Kodaira
  • Masafumi Nishino
  • Mihoko Yamade
  • Takahiro Uotani
  • Shu Sahara
  • Hitomi Ichikawa
  • Takuma Kagami
  • Moriya Iwaizumi
  • Yasushi Hamaya
  • Satoshi Osawa
  • Ken Sugimoto
  • Kazuo Umemura


Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug–drug interactions.


Clopidogrel CYP2C19 Platelet function Proton pump inhibitor Omeprazole Esomeprazole Lansoprazole Rabeprazole Drug–drug interaction Genotype 



Cytochrome p450 2C19


Cytochrome p450 3A4


Intermediate metabolizer


Inhibition of platelet aggregation


Poor metabolizer


Rapid metabolizer



This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (20590718). We thank the staff at the Translational Research Unit, Ms. Takako Toyoda, Ms. Junko Kuroki, Ms. Yoko Akahori, Ms. Yumi Kiyama, Ms Keiko Arasawa, Ms. Saori Oikawa and Ms. Naomi Hashimoto for their help.

Compliance with ethical standards

Conflict of interest

None of the authors had any conflict of interest related to this study.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Takahisa Furuta
    • 1
  • Mitsushige Sugimoto
    • 2
  • Chise Kodaira
    • 2
  • Masafumi Nishino
    • 2
  • Mihoko Yamade
    • 3
  • Takahiro Uotani
    • 2
  • Shu Sahara
    • 2
  • Hitomi Ichikawa
    • 2
  • Takuma Kagami
    • 2
  • Moriya Iwaizumi
    • 2
  • Yasushi Hamaya
    • 2
  • Satoshi Osawa
    • 4
  • Ken Sugimoto
    • 2
  • Kazuo Umemura
    • 5
  1. 1.Center for Clinical ResearchHamamatsu University School of MedicineShizuokaJapan
  2. 2.First Department of MedicineHamamatsu University School of MedicineShizuokaJapan
  3. 3.Department of Clinical OncologyHamamatsu University School of MedicineShizuokaJapan
  4. 4.Department of Endoscopic and Photodynamic MedicineHamamatsu University School of MedicineShizuokaJapan
  5. 5.Department of PharmacologyHamamatsu University School of MedicineShizuokaJapan

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