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    Apixaban Interacts with Haemoglobin: Effects on Its Plasma Levels

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    Type
    Article
    Authors
    Sacco, Monica
    Lancellotti, Stefano
    Berruti, Federico
    Arcovito, Alessandro
    Bellelli, Andrea
    Ricciardelli, Tiziana
    Autiero, Ida
    Cavallo, Luigi cc
    Oliva, Romina
    De Cristofaro, Raimondo
    KAUST Department
    Chemical Science Program
    KAUST Catalysis Center (KCC)
    Physical Science and Engineering (PSE) Division
    Date
    2018-09-20
    Online Publication Date
    2018-09-20
    Print Publication Date
    2018-10
    Permanent link to this record
    http://hdl.handle.net/10754/630547
    
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    Abstract
    The direct oral anticoagulant apixaban (APX), a strong factor Xa inhibitor, binds also to plasma proteins, especially albumin, and minimally to α1-acid glycoprotein. Although APX can cross the red cell membrane, due to its chemical structure, and could bind to haemoglobin (Hb), no investigation was performed on this possible phenomenon that could affect the APX plasma concentration and thus its pharmacokinetics and pharmacodynamics. We addressed this issue by (1) measuring the levels of APX and haematological/biochemical parameters in 90 patients on APX therapy; (2) assessing the effect of APX on oxygen saturation curves of Hb; (3) testing the direct APX binding to Hb by fluorescence spectroscopy and a zinc-induced precipitation of Hb coupled to a reversed-phase high-performance liquid chromatography (HPLC)-based method; and (4) simulating in silico by molecular docking the APX interaction with human Hb. In a multivariable analysis, Hb was the only independent variable significantly and inversely associated in 90 patients with APX peak plasma level, at variance with patients treated with rivaroxaban (n = 86) and dabigatran (n = 34) therapy. APX causes a progressive left-shift of the oxygen dissociation curve of purified Hb solution, with a Kd ≅300 µM. Fluorescence- and HPLC-based assays concordantly showed that APX binds to Hb with a Kd ≅350 µM. Finally, docking simulations showed that APX can fit into in the central cavity of Hb. These findings support the hypothesis that APX does bind to Hb, which, due to its millimolar concentration in blood, can act as ‘buffer’ for the drug and consequently affect its free plasma level.
    Citation
    Sacco M, Lancellotti S, Berruti F, Arcovito A, Bellelli A, et al. (2018) Apixaban Interacts with Haemoglobin: Effects on Its Plasma Levels. Thrombosis and Haemostasis 118: 1701–1712. Available: http://dx.doi.org/10.1055/s-0038-1669920.
    Publisher
    Georg Thieme Verlag KG
    Journal
    Thrombosis and Haemostasis
    DOI
    10.1055/s-0038-1669920
    Additional Links
    https://www.thieme-connect.de/DOI/DOI?10.1055/s-0038-1669920
    ae974a485f413a2113503eed53cd6c53
    10.1055/s-0038-1669920
    Scopus Count
    Collections
    Articles; Physical Science and Engineering (PSE) Division; Chemical Science Program; KAUST Catalysis Center (KCC)

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