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    The binding effect of proteins on medications and its impact on electrochemical sensing: Antipsychotic clozapine as a case study

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    Author
    Banis, G.E.
    Winkler, T.
    Barton, P.
    Date
    2017
    Journal
    Pharmaceuticals
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.3390/ph10030069
    Abstract
    Clozapine (CLZ), a dibenzodiazepine, is demonstrated as the optimal antipsychotic for patients suffering from treatment-resistant schizophrenia. Like many other drugs, understanding the concentration of CLZ in a patient’s blood is critical for managing the patients’ symptoms, side effects, and overall treatment efficacy. To that end, various electrochemical techniques have been adapted due to their capabilities in concentration-dependent sensing. An open question associated with electrochemical CLZ monitoring is whether drug–protein complexes (i.e., CLZ bound to native blood proteins, such as serum albumin (SA) or alpha-1 acid-glycoprotein (AAG)) contribute to electrochemical redox signals. Here, we investigate CLZ-sensing performance using fundamental electrochemical methods with respect to the impact of protein binding. Specifically, we test the activity of bound and free fractions of a mixture of CLZ and either bovine SA or human AAG. Results suggest that bound complexes do not significantly contribute to the electrochemical signal for mixtures of CLZ with AAG or SA. Moreover, the fraction of CLZ bound to protein is relatively constant at 31% (AAG) and 73% (SA) in isolation with varying concentrations of CLZ. Thus, electrochemical sensing can enable direct monitoring of only the unbound CLZ, previously only accessible via equilibrium dialysis. The methods utilized in this work offer potential as a blueprint in developing electrochemical sensors for application to other redox-active medications with high protein binding more generally. This demonstrates that electrochemical sensing can be a new tool in accessing information not easily available previously, useful toward optimizing treatment regimens. Copyright 2017 by the authors. Licensee MDPI, Basel, Switzerland.
    Sponsors
    Research reported in this publication was supported by the National Institute of Mental Health under award number 1R56MH105571, as well as the National Science Foundation Graduate Research Fellowship Program Grant No. DGE00750616.
    Keyword
    Albumin
    Alpha-1 acid-glycoprotein
    Clozapine
    Electrochemistry
    Ultrafiltration
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028552604&doi=10.3390%2fph10030069&partnerID=40&md5=17ff1d8b889fe50063f703f46a3190b4; http://hdl.handle.net/10713/9953
    ae974a485f413a2113503eed53cd6c53
    10.3390/ph10030069
    Scopus Count
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    UMB Open Access Articles 2017

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