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Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease

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Abstract

Background

High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy.

Methods

We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively.

Results

The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 ± 1,476 and 2,960 ± 1,410, respectively, in EM, 4,706 ± 1,417 and 3,239 ± 1,479, respectively, in IM, and 5,402 ± 776 and 4,736 ± 1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 ± 1,436 and 5,100 ± 1,190 AU•min in Expressor and Non-expressor, respectively (P < 0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM.

Conclusions

Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19.

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Acknowledgments

We wish to thank the Medical Secretaries, Aya Miyazaki, Kyoko Watanabe, Hiroko Koga and Yurie Maeda at Kumamoto University Hospital, for collecting the data.

Funding Sources

This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Disclosures

None.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Seiji Hokimoto, Tadasuke Chitose, Michio Mizobe, Tomonori Akasaka, Yuichiro Arima, Koichi Kaikita, Satomi Iwashita & Hisao Ogawa

  2. Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, and Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Kazunori Morita, Hiroko Miyazaki, Kentaro Oniki & Kazuko Nakagawa

  3. General Medicine and Primary Care, Yamaguchi University, Yamaguchi, Japan

    Kunihiko Matsui

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  1. Seiji Hokimoto
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  2. Tadasuke Chitose
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Correspondence to Seiji Hokimoto.

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Hokimoto, S., Chitose, T., Mizobe, M. et al. Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease. Eur J Clin Pharmacol 70, 667–673 (2014). https://doi.org/10.1007/s00228-014-1672-3

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