Pharmaceutical Research

, Volume 15, Issue 5, pp 739–744 | Cite as

Towards the Predictability of Drug-Lipid Membrane Interactions: The pH-Dependent Affinity of Propranolol to Phosphatidylinositol Containing Liposomes

  • Stefanie D. Krämer
  • Annette Braun
  • Christina Jakits-Deiser
  • Heidi Wunderli-Allenspach


Purpose. Prediction of the pH-dependent affinity of (RS)-[3H]propranolol to mixed phosphatidylcholine (PhC)/phosphatidylinositol(Phl) membranes from the partitioning in the single lipid liposome/buffer systems.

Methods. Partition studies in liposome/buffer systems were performed by means of equilibrium dialysis at 37°C between pH 2 and 11 at a molar propranolol to lipid ratio of 10−6 to 10−5 in the membrane.

Results. The Phl membrane more strongly attracts the protonated (RS)-[3H]propranolol than the neutral solute, i.e. the partition coefficient of the protonated base (Pi) is 17′430 ± 1320, P of the neutral compound (Pn) is 3110 ± 1650. In the PhC-liposome system Pi is 580 ± 17, Pn 1860 ± 20. The partition coefficients show an exponential dependence on the molar Phl fraction in mixed liposomes. The partitioning in mixed PhC/Phl membranes is predictable from Pn and Pi in the single lipid liposome systems.

Conclusions. The negative charge of biological lipid membranes causes strong electrostatic interactions with positively charged solutes. This strong attraction is not predictable from the octanol/buffer partition system, but it is important regarding drug accumulation in the tissue and drug attraction by certain lipids in the vicinity of membrane proteins.

lipophilicity partitioning liposome propranolol drug-lipid membrane interactions phosphatidylinositol 


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  1. 1.
    B. Testa, P. A. Carrupt, P. Gaillard, F. Billois, and P. Weber. Lipophilicity in molecular modeling. Pharm. Res. 13:335–343 (1996).PubMedGoogle Scholar
  2. 2.
    W. K. Surewicz and W. Leyko. Interaction of propranolol with model lipid membranes. Monolayer, spin label and fluorescence spectroscopy studies. Biochim. Biophys. Acta 643:387–397 (1981).PubMedGoogle Scholar
  3. 3.
    G.V. Betageri and J. A. Rogers. The liposome as a distribution model in QSAR studies. Int. J. Pharm. 46:95–102 (1988).Google Scholar
  4. 4.
    J. M. Canaves, J. Aleu, M. Lejarreta, J. M. Gonzalezros, and J. A. Ferragut. Effects of pH on the kinetics of the interaction between anthracyclines and lipid bilayers. Eur. Biophys. J. 26:427–431 (1997).Google Scholar
  5. 5.
    S. D. Krämer, C. Jakits-Deiser, and H. Wunderli-Allenspach. Free fatty acids cause pH-dependent changes in drug-lipid membrane interactions around physiological pH. Pharm. Res. 14:827–832 (1997).PubMedGoogle Scholar
  6. 6.
    C. Ottiger. Partition behaviour of acids, bases and neutral drugs with liposomes, IAM-HPLC and 1-octanol. Dissertation ETH Zũrich, Switzerland #12439 (1997).Google Scholar
  7. 7.
    S. D. Krämer and H. Wunderli-Allenspach. The pH-dependence in the partitioning behaviour of (RS)-[3H]Propranolol between MDCK cell lipid vesicles and buffer. Pharm. Res. 13:1851–1855 (1996).PubMedGoogle Scholar
  8. 8.
    M. J. Hope, M. B. Bally, G. Webb, and P. R. Cullis. Production of large unilamellar vesicles by a rapid extrusion procedure. Characterization of size distribution, trapped volume and ability to maintain a membrane potential. Biochim. Biophys. Acta 812:55–65 (1985).Google Scholar
  9. 9.
    G. M. Pauletti and H. Wunderli-Allenspach. Partition coefficients in vitro: artificial membranes as a standardized distribution model. Eur. J. Pharm. Sci. 1:273–282 (1994).Google Scholar
  10. 10.
    M. Takayama, S. Itoh, T. Nagasaki, I. Tanimizu. A new enzymatic method for the determination of serum choline-containing phospholipids. Clin. Chim. Acta 79:93–98 (1977).PubMedGoogle Scholar
  11. 11.
    W. W. Christie. Separation of lipid classes by high-performance liquid chromatography with the “mass detector”. J. Chromatogr. 361:396–399 (1986).PubMedGoogle Scholar
  12. 12.
    J. A. Berden, R. W. Barker, and G. K. Radda. NMR studies on phospholipid bilayers: some factors affecting lipid distribution. Biochim. Biophys. Acta 375:186–208 (1975).PubMedGoogle Scholar
  13. 13.
    D. Marsh. Handbook of lipid bilayers, CRC Press, Boston, 1990.Google Scholar
  14. 14.
    R. C. MacDonald and A. D. Bangham. Comparison of double layer potentials in lipid monolayers and lipid bilayer membranes. J. Membr. Biol. 7:29–53 (1971).Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Stefanie D. Krämer
    • 1
  • Annette Braun
    • 1
  • Christina Jakits-Deiser
    • 1
  • Heidi Wunderli-Allenspach
    • 1
  1. 1.Biopharmacy, Department of Pharmacy, ETH ZürichZürichSwitzerland

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