Journal
MOLECULAR PHARMACEUTICS
Volume 13, Issue 4, Pages 1251-1257Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00783
Keywords
ocular melanin; drug binding assays; multiple classes of independent sites; bi-Langmuir isotherm; Langmuir-Freundlich isotherm; Sips isotherm; site energy distribution function; Scatchard plot; chloroquine; metoprolol
Funding
- Ministry of Economic Affairs and Competitiveness
- FEDER [MAT2012-32084]
- Generalitat Valenciana [Prometeo/GV/2012/0069]
- Academy of Finland
- Sigrid Juselius Foundation
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Melanin has a high binding affinity for a wide range of drugs. The determination of the melanin binding capacity and its binding affinity are important, e.g., in the determination of the ocular drug distribution, the prediction of drug effects in the eye, arid the trans-scleral drug delivery. The binding parameters estimated from a given data set vary significantly when using different isotherms or different nonlinear fitting methods. In this work, the commonly used bi-Langmuir isotherm, which assumes two classes of independent sites, is confronted with the Sips isotherm. Direct, log log, and Scatchard plots are used, and the interpretation of the binding curves in the latter is critically analyzed. In addition to the goodness of fit, the emphasis is placed on the physical meaning of the binding parameters. The bi-Langmuir model imposes a bimodal distribution of binding energies for the sites on the Melanin granules, but the actual distribution is most likely continuous and unimodal, as assumed by the Sips isotherm. Hence, the latter describes more accurately the distribution of binding energies and also the experimental results of melanin binding to drugs and metal ions. Simulations are used to show that the existence of two classes of sites cannot be confirmed on the sole basis of the shape of the binding curve in the Scatchard plot, and that serious doubts may appear on the meaning of the binding parameters of the bi-Langmuir model. Experimental results of melanin binding to chloroquine and metoprolol are used to illustrate the importance of the choice of the binding isotherm and of the method used to evaluate the binding parameters.
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