Statins in therapy: Understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies

Abstract

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the various statins can undergo endogenous oxidative metabolism. The absolute chemical hardness is also an indicator of the stability of the statins, and may be a useful indicator for drug design.

Clinically relevant drug interactions between statins and antidepressants

“…The statins are a class of amphiphilic drugs subdivided into lipophilic agents (ie atorvastatin, fluvastatin, lovastatin and simvastatin) that can enter directly in cells and hydrophilic agents (ie pitavastatin, pravastatin and rosuvastatin) that need protein carriers to cross cell layer. Lovastatin and simvastatin are ingested as lipophilic lactone pro‐drugs, whereas other statins are administered as active acid forms …”

Statins and breast cancer stage and mortality in the Women’s Health Initiative

“…Lovastatin, simvastatin, atorvastatin and fluvastatin are all lipophilic statins, whereas pravastatin is a hydrophilic statin. Fluvastatin and lovastatin are low-potency statins, pravastatin is a medium-potency statin, and simvastatin and atorvastatin are high-potency statins [23, 24]. Updated information on statin use collected at subsequent participant visits were used to measure statin use as a time-dependent exposure.…”

Effects of Statins on Left Ventricular Diastolic Function in Patients with Dyslipidemia and Diastolic Dysfunction (Stat-LVDF Study)

“…The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. 20) Bioavailability of statins, such as absorption efficiency, transferability to tissues, and retentive property by pharmacokinetics studies should be considered in addition to the classification of "hydrophilic" or "lipophilic. "…”