Magnesium cation effect on passive diffusion of statin molecules: Molecular chromatography approach

Recently, immobilized artificial membranes (IAMs) have been introduced as HPLC column packing materials. IAMs consist of phosphatidylcholine residues, the most common phospholipids in natural membranes, covalently bound to silica propylamine and consequently mimic fluid phospholipid bilayer. Thus, the immobilized artificial membrane provided a biophysical model system to study the passive diffusion of the statin molecules through the cellular membrane. Statins or 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA R) inhibitors are widely used for reducing the circulating atherogenic lipid fractions and decreasing cardiovascular morbidity and mortality. This paper describes magnesium cation (Mg2+) effect on five statin molecules (pravastatin, mevastatin, atorvastatin, simvastatin and fluvastatin)–IAM surface association using a molecular chromatography approach. An analysis of the thermodynamics (i.e. enthalpy (ΔH°), entropy (ΔS°*)) of the interaction of the statin molecules with the immobilized monolayer was also carried out. The ΔH° and ΔS°* values were negative due to van der Waals interactions and hydrogen bonding between the statin molecules with the polar head groups of phospholipid monolayer (polar retention effect). However, the increase of statin–IAM association, with the Mg2+ concentration increase, was associated with an increase of these thermodynamic data. This explains that this interaction was also governed by hydrophobic and electrostatic bonds which became preponderant. The statin elution order was: Pravastatin ⋘< Mevastatin ≪ Atorvastatin ⋘ Simvastatin < Fluvastatin. This result confirmed that pravastatin, which exhibited the lowest association with the lipid monolayer, was taken up by a membrane transporter. It appeared equally that Mg2+ supplementation (Mg2+ concentration range 0.0–2.6 mmol L−1, including its biological concentration range, i.e. 0.75–0.90 mmol L−1) could increase the statin passive diffusion into hepatocytes and their pharmacological actions on cholesterol biosynthesis.