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Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy

The Pharmacogenomics Journal volume 13, pages 507–513 (2013)Cite this article

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Abstract

Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53±17 years) receiving high-dose MTX (5.13±1.88 g m−2 in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 −24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the −24T allele as compared with noncarriers: 8.6±2.2 vs 6.7± 2.5 l h−1, P<0.01 and 30.7±7.7 vs 22.1±8.8 l, P<0.001, respectively. Consequently, −24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration.

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Acknowledgements

The study was sponsored by Assistance-Publique Hôpitaux de Paris.

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Authors and Affiliations

  1. Aix-Marseille université, Service de Pharmacologie Médicale et Clinique, AP-HM, Hôpital de la Timone, Marseille, France

    N Simon & A Marsot

  2. UPMC Univ Paris 06, UMR_S 956, Paris, France

    E Villard & J-S Hulot

  3. Department of Haematology, Pitié-Salpêtrière University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    S Choquet & V Leblond

  4. Department of Neurology, Pitié-Salpêtrière University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    H-X Khe

  5. Department of Pharmacology, Pitié-Salpêtrière University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    N Zahr, P Lechat & J-S Hulot

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Correspondence to J-S Hulot.

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Simon, N., Marsot, A., Villard, E. et al. Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy. Pharmacogenomics J 13, 507–513 (2013). https://doi.org/10.1038/tpj.2012.37

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  • DOI: https://doi.org/10.1038/tpj.2012.37

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