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Pharmaceuticals 2017, 10(3), 69; doi:10.3390/ph10030069

The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study

1
Department of Bioengineering, University of Maryland, 2201 J.M. Patterson Hall, College Park, MD 20742, USA
2
Institute for Bioscience and Biotechnology Research, University of Maryland, Suite 5115 Plant Sciences Building, College Park, MD 20742, USA
3
Maryland Psychiatric Research Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore MD 21201, USA
4
Department of Biomedical Engineering, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
5
Institute for Systems Research, University of Maryland, 2173 A.V. Williams Building, College Park, MD 20742, USA
Present address: Department of Micro- and Nanosystems, KTH Royal Institute of Technology, 114 28 Stockholm, Sweden.
*
Author to whom correspondence should be addressed.
Received: 12 June 2017 / Revised: 27 July 2017 / Accepted: 29 July 2017 / Published: 1 August 2017
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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. View Full-Text
Keywords: electrochemistry; clozapine; albumin; alpha-1 acid-glycoprotein; ultrafiltration electrochemistry; clozapine; albumin; alpha-1 acid-glycoprotein; ultrafiltration
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Banis, G.E.; Winkler, T.; Barton, P.; Chocron, S.E.; Kim, E.; Kelly, D.L.; Payne, G.F.; Ben-Yoav, H.; Ghodssi, R. The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study. Pharmaceuticals 2017, 10, 69.

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