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Kinetics and Thermodynamics of Chlorpromazine Interaction with Lipid Bilayers: Effect of Charge and Cholesterol
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    Kinetics and Thermodynamics of Chlorpromazine Interaction with Lipid Bilayers: Effect of Charge and Cholesterol
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    Chemistry Department FCTUC, Largo D. Dinis, Rua Larga, 3004-535 Coimbra, Portugal
    Institute of Biocomputation and Physics of Complex Systems (BIFI), Universidad de Zaragoza, 50018 Zaragoza, Spain, Unidad Asociada BIFI-IQFR, CSIC, Zaragoza, Spain
    § Fundación ARAID, Diputación General de Aragón, Spain
    Instituto de Tecnologia Química e Biológica − UNL, Av. da República-EAN, 2780-157 Oeiras, Portugal
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2012, 134, 9, 4184–4195
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    https://doi.org/10.1021/ja209917q
    Published January 31, 2012
    Copyright © 2012 American Chemical Society

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    Passive transport across cell membranes is the major route for the permeation of xenobiotics through tight endothelia such as the blood–brain barrier. The rate of passive permeation through lipid bilayers for a given drug is therefore a critical step in the prediction of its pharmacodynamics. We describe a detailed study on the kinetics and thermodynamics for the interaction of chlorpromazine (CPZ), an antipsychotic drug used in the treatment of schizophrenia, with neutral and negatively charged lipid bilayers. Isothermal titration calorimetry was used to study the partition and translocation of CPZ in lipid membranes composed of pure POPC, POPC:POPS (9:1), and POPC:Chol:POPS (6:3:1). The membrane charge due to the presence of POPS as well as the additional charge resulting from the introduction of CPZ in the membrane were taken into account, allowing the calculation of the intrinsic partition coefficients (KP) and the enthalpy change (ΔH) associated with the process. The enthalpy change upon partition to all lipid bilayers studied is negative, but a significant entropy contribution was also observed for partition to the neutral membrane. Because of the positive charge of CPZ, the presence of negatively charged lipids in the bilayer increases both the observed amount of CPZ that partitions to the membrane (KPobs) and the magnitude of ΔH. However, when the electrostatic effects are discounted, the intrinsic partition coefficient was smaller, indicating that the hydrophobic contribution was less significant for the negatively charged membrane. The presence of cholesterol strongly decreases the affinity of CPZ for the bilayer in terms of both the amount of CPZ that associates with the membrane and the interaction enthalpy. A quantitative characterization of the rate of CPZ translocation through membranes composed of pure POPC and POPC:POPS (9:1) was also performed using an innovative methodology developed in this work based on the kinetics of the heat evolved due to the interaction of CPZ with the membranes.

    Copyright © 2012 American Chemical Society

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    Characterization of LUVs size, ζ potential, and multilamellarity. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2012, 134, 9, 4184–4195
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ja209917q
    Published January 31, 2012
    Copyright © 2012 American Chemical Society

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