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Pharmaceutical Research

, Volume 24, Issue 8, pp 1457–1472 | Cite as

Comparing the Lipid Membrane Affinity and Permeation of Drug-like Acids: The Intriguing Effects of Cholesterol and Charged Lipids

  • Anita V. Thomae
  • Tamara Koch
  • Christian Panse
  • Heidi Wunderli-Allenspach
  • Stefanie D. Krämer
Research Paper

Abstract

Purpose

Lipid bilayers regulate the passage of solutes into and between cellular compartments. A general prerequisite for this passage is the partitioning of the solute into the bilayer. We investigated the relationship between bilayer partitioning and permeation of three drug-like acids in liposomal systems consisting of phosphatidylcholine alone or mixed with cholesterol or charged lipids.

Materials and Methods

Bilayer partitioning was determined by equilibrium dialysis. Bilayer permeation was studied with a luminescence assay which is based on the energy transfer of the permeant to intraliposomal terbium(III).

Results

The influence of the lipid composition on the pH-dependent membrane affinity was in accordance with the membrane rigidity and possible electrostatic interactions between the acids and the lipids. However, there was no direct relationship between membrane affinity and permeation. This seeming discrepancy was closer analyzed with numerical simulations of the permeation process based on the single rate constants for partitioning and translocation. The simulations were in line with our experimental findings.

Conclusions

Depending on the single rate constants and on the geometry of the system, lipid bilayer permeation may positively, negatively or not correlate with the bilayer affinity of the permeant.

Key words

cholesterol lipid bilayer liposome membrane affinity membrane permeation 

Abbreviations

AA

Anthranilic acid

ACA

aromatic carboxylic acid

Chol

Cholesterol

DCBA

3,5-Dichlorbenzoic acid

PhC

Phosphatidylcholine

PhI

Phosphatidylinositol

SA

Salicylic acid

StAm

Stearylamine

2-OH-NA

2-Hydroxynicotinic acid

Notes

Acknowledgement

We would like to thank Maja Günthert for experimental support as well as Knud Zabrocki and Marian Brandau (Martin-Luther-University Halle, Germany) for their advice concerning the mathematical solution of the differential equation system.

Supplementary material

11095_2007_9263_MOESM1_ESM.doc (3.9 mb)
Supplement 1 Electronic supplementary material (4mb)

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Anita V. Thomae
    • 1
  • Tamara Koch
    • 1
  • Christian Panse
    • 2
  • Heidi Wunderli-Allenspach
    • 1
  • Stefanie D. Krämer
    • 1
  1. 1.Institute of Pharmaceutical SciencesDepartment of Chemistry and Applied Biosciences, ETH ZurichZurichSwitzerland
  2. 2.Functional Genomics CenterUNI/ETH ZurichZurichSwitzerland

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