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Related Experiment Videos

Blood-brain barrier permeation: molecular parameters governing passive diffusion

H Fischer1, R Gottschlich, A Seelig

  • 1Department of Biophysical Chemistry, Biocenter of the University of Basel, Klingelbergstr, 70, CH-4056 Basel, Switzerland.

The Journal of Membrane Biology
|October 10, 1998
PubMed
Summary

Molecular cross-sectional area is key for blood-brain barrier penetration. Surface activity measurements reveal three compound groups based on air-water partition coefficient and cross-sectional area, predicting passive diffusion across the blood-brain barrier.

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Area of Science:

  • Physical Chemistry
  • Biophysics
  • Pharmacology

Background:

  • The blood-brain barrier (BBB) restricts passive diffusion of many compounds into the central nervous system.
  • Understanding factors governing BBB permeability is crucial for drug design and delivery.
  • Previous studies utilized lipid membrane-water partition coefficients (Klw) to assess permeability.

Purpose of the Study:

  • To characterize compounds based on surface activity and predict their ability to cross the BBB via passive diffusion.
  • To establish correlations between air-water partition coefficient (Kaw), critical micelle concentration (CMCD), and cross-sectional area (AD) with BBB penetration.
  • To investigate the role of molecular cross-sectional area and interfacial tension in membrane permeation.

Main Methods:

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  • Surface activity measurements were performed on 53 compounds with known BBB penetration.
  • Key parameters quantified: air-water partition coefficient (Kaw), critical micelle concentration (CMCD), and cross-sectional area (AD).
  • A 3D plot was used to visualize compound grouping based on these parameters.

    • Main Results:

    • Three distinct compound groups were identified based on AD and Kaw, correlating with BBB permeability.
    • Hydrophobic compounds with large AD (>80 Ų) did not cross the BBB.
    • Compounds with moderate AD (≈50 Ų) and lower Kaw readily crossed the BBB.
    • Hydrophilic compounds (AD <50 Ų) crossed only at high concentrations.
    • A correlation was established between Klw and Kaw, incorporating molecular cross-sectional area and bilayer pressure (pibi).
    • Membrane partitioning decreased exponentially with increasing AD, described by Klw = const. Kaw exp(-ADpibi/kT).

    Conclusions:

    • Molecular cross-sectional area at the interface is a primary determinant of BBB passive diffusion.
    • Surface activity parameters (Kaw, CMCD, AD) effectively predict BBB penetration.
    • The findings are applicable to surface-active molecules with specific pKa ranges (acids > 4, bases < 10).