Journal
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
Volume 868, Issue 1-2, Pages 20-27Publisher
ELSEVIER
DOI: 10.1016/j.jchromb.2008.03.034
Keywords
statins; HPLC; IAM; binding; thermodynamic
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Many studies have demonstrated that the statin beneficial effects on cardiovascular diseases like coronary are linked to their hypocholesterolemic properties. These lipid-lowering drugs are the first-line pharmacologic therapy for hypercholesterolemia. In this paper, the interaction of a series of statin molecules STCOOH (pravastatin (prava), mevastatin (meva), simvastatin (simva) and fluvastatin (fluva)) with a phosphatidylcholine monolayer immobilized on to porous silica particles has been studied using a biochromatographic approach (molecular chromatography). The immobilized artificial membrane (IAM) provided a biophysical model system to study the binding of the statin molecules to a lipid membrane. For all the test statin molecules, linear retention plots were observed at all temperatures. An analysis of the thermodynamics (i.e., enthalpy (Delta H degrees), entropy (Delta S degrees*)) of the interaction of the statin molecules with the immobilized monolayer was also carried out. The Delta H degrees, and Delta S degrees* values were negative due to van der Waals interactions and hydrogen bonding between the statin molecules with the polar head groups of the phospholipid monolayer (polar retention effect). The statin elution order was: Prava <<< Mleva < Atorva << Simva < Fluva. This result associated with IC50 data of each statin molecule confirmed that pravastatin, which exhibited the lowest association with the lipid monolayer, was taken up by a membrane transporter. In addition, the logarithm of the statin retention factor with the lipid membrane extrapolated to a total aqueous bulk solvent at pH 7.0 (log k'(W-IAM)) was measured and compared to the octanol-water partition coefficient (logP). The observed significant correlation showed an affinity enhanced with the increase in the molecule lipophilicity and confirmed that the hydrophobic forces played an important role in the statin molecule-biomembrane association mechanism. As well, the affinity of STCOOH to IAM is high and changes slightly with the bulk solvent pH, because the number of protons linked to binding is low. This confirmed the importance to take into account the electrostatic interaction in this association mechanism. At pHs lower than approximate to 7.0, the binding process is accompanied by protons release and at higher pHs protons are taken up. A change in the phospholipid monolayer phosphate group pK(a) has been proposed to contribute to the positive number of protons exchanged at pHs higher than approximate to 7.0. This demonstrated that this phosphate residue could function as a general base/proton shuttle by facilitating the deprotonation of STCOOH, i.e., this hyper-reactive residue in the IAM surface could play a catalytic function. (c) 2008 Elsevier B.V. All rights reserved.
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