Modification of amphotericin B's therapeutic index by increasing its association with serum high-density lipoproteins.
AmpB remains one of the drugs of choice in the treatment of systemic fungal infection; however, its therapy is limited by the development of renal toxicity. When AmpB was incorporated into negatively charged liposomes composed of DMPC and DMPG (L-AmpB), it was less toxic but as effective as free AmpB. However, the mechanism of L-AmpB's enhanced therapeutic index remains unknown. We have demonstrated that AmpB predominantly associates with HDL when incorporated into positively and negatively charged liposomes. To further understand the therapeutic importance of AmpB predominantly associating with HDL, we next examined the influence of lipoproteins on the antifungal activity and renal cytotoxicity of AmpB. The antifungal activity of AmpB and L-AmpB was not altered in the presence of HDL or LDL. The reduced nephrotoxicity associated with the use of L-AmpB, however, was related to a decreased uptake of AmpB by renal cells when AmpB was associated with HDL, and it may be a result of the low expression of HDL receptors in the LLC PK1 renal cells.
Wasan
K M
KM
Department of Cell Biology, Cleveland Clinic Foundation, Ohio 44195.
Lopez-Berestein
G
G
D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D002460:Cell Line; D007674:Kidney Diseases / Q000139:chemically induced; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008081:Liposomes; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism; D013696:Temperature; D014018:Tissue Distribution
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008081:Liposomes; D011973:Receptors, LDL; D000666:Amphotericin B