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The drug distribution process within the human body is a complex interplay of various physicochemical properties inherent to the drugs. These properties, including molecular size, ionization degree, partition coefficient, and stereochemical nature, significantly impact how drugs permeate biological membranes to reach their target tissues.
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Body:After oral administration, poor permeability often limits the rate at which drugs are absorbed through the intestinal epithelium. Enhancing drug permeability is crucial for effective therapy, and several strategies have been developed to overcome this challenge.One effective strategy involves the use of lipid-based formulations. These formulations enhance dissolution and solubility, targeting physiological mechanisms to increase drug absorption. This includes stimulating bile salt...
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Link between Membrane Composition and Permeability to Drugs.

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Area of Science:

  • Computational chemistry
  • Biophysics
  • Pharmacology

Background:

  • Accurate prediction of small molecule membrane permeability is vital for drug discovery.
  • Understanding the thermodynamics and kinetics of permeant translocation across lipid bilayers is essential.
  • Lipid bilayer composition, particularly cholesterol content, influences drug permeability.

Purpose of the Study:

  • To estimate the membrane permeability of three diverse drug molecules (9-anthroic acid, 2',3'-dideoxyadenosine, hydrocortisone) in pure POPC and POPC:cholesterol bilayers.
  • To investigate the impact of cholesterol on drug permeability and identify underlying molecular mechanisms.
  • To validate computational methods for predicting membrane permeability.

Main Methods:

  • Utilized free-energy calculations (2-5 μs) to determine thermodynamics of permeation.
  • Employed time-fractional Smoluchowski equation to model diffusivity across the bilayer.
  • Compared computational estimates with experimental data from egg-lecithin bilayers.

Main Results:

  • Calculated permeabilities for ANA, DDA, and HYL generally agreed within an order of magnitude with experimental values.
  • Hydrocortisone (HYL) showed a significant, ~600-fold decrease in permeability in POPC:cholesterol compared to pure POPC bilayers.
  • Permeability differences for ANA and DDA between the two bilayer types were less than a factor of 10.
  • Cholesterol-rich bilayers exhibited lower permeabilities due to increased free-energy barriers.

Conclusions:

  • Rigorous free-energy calculations and fractional-diffusion models accurately predict membrane permeability.
  • Cholesterol significantly alters membrane permeability, particularly for large amphiphilic molecules like hydrocortisone, potentially via different translocation mechanisms.
  • These computational approaches reveal molecular insights into how membrane composition affects drug permeability, aiding drug discovery efforts.