Skip to main content
SpringerLink
Log in

Activity and kinetics of dissociation and transfer of amphotericin B from a novel delivery form

  • Published:
AAPS PharmSci Aims and scope Submit manuscript

Abstract

Recently it has been demonstrated that moderate heat treatment of Amphotericin B/deoxycholate solutions (HAmB-DOC) leads to a therapeutically interesting supramolecular rearrangement that can be observed by significant changes in light scattering, CD, and absorbance. In this study, we continue the investigation of the physical properties of this new form by evaluating the activity and kinetics of dissociation and dispersion of HAmB-DOC and AmB-DOC in saline, serum, and in model mammalian or fungal lipid biomimetic membrane vesicles. Stopped-flow spectrophotometry combined with singular value decomposition (SVD) and global analysis were used to resolve the components of this process. The dissociation kinetics for both states are complex, requiring multiexponential fits, vet in most cases SVD indicates only two significant changing species representing the monomer and the aggregate. The kinetic mechanism could involve dissociation of monomers from coexisting spectroscopically similar but structurally distinct aggregates or sequential rearrangements in supramolecular structure of aggregates. Rate constants and amplitudes of dissociation from aggregates to monomer in buffer, whole serum, 10% cholesterol, and ergosterol membrane vesicles are generally greater for AmB-DOC, demonstrating its greater kinetic instability. In addition, at comparable low concentrations, HAmB-DOC and AmB-DOC are nearly equally active at promoting cation selective permeability in ergosterol-containing membranes; however, HAmB-DOC is much less active against mammalian mimetic cholesterol-containing vesicles, despite a higher level of self-association, supporting previous observations that there exists a specific “toxic aggregate” structure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hartsel, S. and J. Bolard, Amphotericin B: new life for an old drug. Trends Pharmacol Sci. 1996;17:445–449.

    Article  CAS  PubMed  Google Scholar 

  2. Hiemenz, J.W. and T.J. Walsh, Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis. 1996;22:133–144.

    Article  Google Scholar 

  3. Brajburg, J. and J. Bolard, Carrier effects on biological activity of amphotericin B. Clin Microbiol Rev. 1996;9:512–531.

    Google Scholar 

  4. Bolard, J., P. Legrand, F. Heitz, and B. Cybulska, One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium. Biochemistry. 1991;30:5707–5715.

    Article  CAS  PubMed  Google Scholar 

  5. Legrand, P., E.A. Romero, B.E. Cohen, and J. Bolard, Effects of Aggregation and Solvent on the Toxicity of Amphotericin-B to Human Erythrocytes. Antimicrob Agents Chemother. 1992;36:2518–2522.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Lamy-Freund, M.T., V.F.N. Ferreira A. Faljonialario, and S. Schreier, Effect of Aggregation on the Kinetics of Autoxidation of the Polyene Antibiotic Amphotericin-B. J Pharm Sci. 1993;82:162–166.

    Article  CAS  PubMed  Google Scholar 

  7. Lamy-Freund, M.T., V.F. Ferreira, and S. Schreier, Mechanism of mactivation of the polyene antibiotic amphotericin B. Evidence for radical formation in the process of autooxidation. J Antibiot (Tokyo) 1985;38:753–757.

    Article  CAS  Google Scholar 

  8. Gaboriau, F., M. Cheron, L. Leroy, and J. Bolard, Physico-Chemical properties of the heat-induced ‘superaggregates’ of amphotericin B. Biophysical Chemistry. 1997;66:1–12.

    Article  CAS  PubMed  Google Scholar 

  9. Gaboriau, F., M. Cheron, C. Petit, and J. Bolard, Heat-induced superaggregation of amphotericin B reduces its in vitro toxicity: a new way to improve its therapeutic index. Antimicrob Agets Chemother. 1997;41:2345–2351.

    CAS  Google Scholar 

  10. Petit, C., V. Yardley, F. Gaboriau, J. Bolard, and S.L. Croft. Activity of a heat-induced reformulation of amphoteriein B deoxycholate (fungizone) against Leishmania donovani [In Process Citation]. Antimicrob Agents Chemother. 1999;43:390–392.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Ruckwardt, T., A. Scott, J. Scott, P. Mikulecky, and S.C. Hartsel, Lipid and stress dependence of amphotericin B ion selective channels in sterol-free membranes. Biochim Biophys Acta. 1998;1372:283–288.

    Article  CAS  PubMed  Google Scholar 

  12. Henry, E.R.a.H., J., Singular Value decomposition: Application to Analysis of Experimental Data, in Numerical Computer Methods, L.a.J. Brand, M. L., Editor. 1992, Academic Press, Inc.: p. 129–192.

  13. Fujii, G., J.E. Chang, T. Coley, and B. Steere, The formation of amphotericin B ion channels in lipid bilayers. Biochemistry. 1997;36:4959–4968.

    Article  CAS  PubMed  Google Scholar 

  14. Lamy-Freund, M.T., S. Schreier, R.M. Peitzsch, and W.F. Reed, Characterization and time dependence of amphotericin B: deoxycholate aggregation by quasielastic light scattering. J Pharm Sci. 1991;80:262–2666.

    Article  CAS  PubMed  Google Scholar 

  15. Hartsel, S.C., C. Hatch, W. Ayenew, How Does Amphotericin B Work?: Studies on Model Systems. Journal of Liposome Research. 1993;3:377–408.

    Article  CAS  Google Scholar 

  16. Legrand, P., M. Cheron, L. Leroy, and J. Bolard, Release of amphotericin B from delivery systems and its action against fungal and mammalian cells. Journal of Drug Targeting. 1997;4:311–319.

    Article  CAS  PubMed  Google Scholar 

  17. Lamy-Freund, M.T., V.F. Ferreira, and S. Schreier, Polydispersity of aggregates formed by the polyene antibiotic amphotericin B and deoxycholate. A spin label study. Biochim Biophys Acta. 1989;981:207–212.

    Article  CAS  PubMed  Google Scholar 

  18. Barwicz, J. and P. Tancrede, The effect of aggregation state of amphotericin-B on its interactions with cholesterol- or ergosterol-containing phosphatidylcholine monolayers. Chem Phys Lipids. 1997;85:145–155.

    Article  CAS  PubMed  Google Scholar 

  19. Tancrede, P., J. Barwicz, S. Jutras, and I. Gruda, The effect of surfactants on the aggregation state of Amphotericin B. Biochim Biophys Acta. 1990;1030:289–95.

    Article  CAS  PubMed  Google Scholar 

  20. Ceryak, S., B. Bouscarel, and H. Fromm, Comparative binding of bile acids to serum lipoproteins and albumin. J Lipid Res. 1993;34:1661–1674.

    CAS  PubMed  Google Scholar 

  21. Meyuhas, D. and D. Lichtenberg, The effect of albumin on the state of aggregation and phase transformations in phosphatidylcholine-sodium cholate mixtures. Biochim Biophys Acta. 1995;1234:203–213.

    Article  PubMed  Google Scholar 

  22. Passing, R. and D. Schubert. The binding of deoxycholic acid to band 3 protein from human erythrocyte membranes and to bovine serum albumin. Hoppe Seylers Z Physiol Chem. 1983;364:219–226.

    Article  CAS  PubMed  Google Scholar 

  23. Romanini, D., B. Farruggia, and G. Pico, Absorption and fluorescence spectra of polyene antibiotics in the presence of human serum albumin. Biochem Mol Biol Int. 1998;44:595–603.

    CAS  PubMed  Google Scholar 

  24. Ridente, Y., J. Aubard, and J. Bolard, Absence in amphotericin Bspiked human plasma of the free monomeric drug, as detected by SERS FEBS Lett. 1999;446:283–286.

    Article  CAS  PubMed  Google Scholar 

  25. Petit, C., V. Yardley, F. Gaboriau, J. Bolard, and S.L. Croft, Activity of a heat-induced reformulation of amphotericin B deoxycholate (fungizone) against Leishmania donovani. Antimicrob Agents Chemother. 1999;43:390–392.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Petit, C., M. Cheron, V. Joly, J.M. Rodrigues, J. Bolard, and F. Gaboriau, In-vivo therapeutic efficacy, in experimental murine mycoses of a new formulation of deoxycholate-amphotericin B obtained by mild heating [In Process Citation]. J Antimicrob Chemother. 1998;42:779–785.

    Article  CAS  PubMed  Google Scholar 

  27. Cutaia, M., S.R. Bullard, K. Rudio, and S. Rounds, Characteristics of Amphotericin-B Induced Endothelial Cell Injury. J Lab Clin Med. 1993;121:244–256.

    CAS  PubMed  Google Scholar 

  28. Brajtburg, J., Elberg, S., Bolard, J., Kobayashi, G. S., Levy, R. A., Ostlund, R. E., Jr., Schlessinger, D., and G. Medoff Interaction of plasma proteins and lipoproteins with amphotericin B. J Infect Dis. 1984;149:986–997 (1) Brajtburg, J., Elberg, S.

    Article  CAS  PubMed  Google Scholar 

  29. Chavanet, P., V. Joly, D. Rigand, J. Bolard, C. Carbon, and P. Yeni, Influence of Diet on Experimental Toxicity of Amphotericin B Deoxycholate. Antimicrob Agents Chemother. 1994;38:963–968.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Vertut-Doi, A., S.I. Ohnishi, and J. Bolard, The endocytic process in CHO cells, a toxic pathway of the polyene antibiotic amphotericin B. Antimicrob Agents Chemother. 1994;38:2373–2379.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Wasan, K.M., R.E. Morton, M.G. Rosenblum, and G. Lopez-Berestein, Decreased toxicity of liposomal amphotericin B due to association of amphotericin B with high-density lipoproteins: role of lipid transfer protein. J Pharm Sci. 1994;83:1006–1010.

    Article  CAS  PubMed  Google Scholar 

  32. Wasan, K.M. and G. Lopezberestein, The interaction of liposomal amphotericin B and serum lipoproteins within the biological milieu, J Drug Target. 1994;2:373–380.

    Article  CAS  PubMed  Google Scholar 

  33. Wasan, K.M. and J.S. Conklin, Enhanced amphotericin B nephrotoxicity in intensive care patients with elevated levels of low-density lipoprotein cholesterol. Clin Infect Dis. 1997;24:78–80.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin-Eau Claire, Phillips 461, 54702-4004, Eau Claire, Wisconsin

    Bradley Baas, katie Kindt, Angela Scott, Jessica Scott, Peter Mikulecky & Scott C. Hartsel

Authors
  1. Bradley Baas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. katie Kindt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jessica Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Mikulecky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Scott C. Hartsel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott C. Hartsel.

Additional information

Published: August 21, 1999.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baas, B., Kindt, k., Scott, A. et al. Activity and kinetics of dissociation and transfer of amphotericin B from a novel delivery form. AAPS PharmSci 1, 10 (1999). https://doi.org/10.1208/ps010310

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/ps010310

Keywords

Search

Navigation