Plasma Lipoprotein Distribution of Liposomal Nystatin Is Influenced by Protein Content of High-Density Lipoproteins

Cassidy, Shawn M.; Strobel, Frank W.

doi:10.1128/aac.42.8.1878

Cited by 29 publications

(19 citation statements)

References 36 publications

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“…8,18 This rationale is further substantiated by recent findings which demonstrated that as the amount of HDL protein decreased, the percent of nystatin recovered within the HDL fraction proportionally decreased following the incubation of liposomal nystatin. 19 The studies presented in this paper determine the plasma lipoprotein distribution of AmpB and ABLC following incubation in plasma from different human subjects with varying total and lipoprotein lipid concentrations and address the role of lipoprotein lipid and protein content on the distribution of AmpB to plasma lipoproteins.…”

Section: Introductionmentioning

confidence: 99%

Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content

Kennedy

1999

Journal of Pharmaceutical Sciences

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The purpose of this study was to determine the plasma lipoprotein (LP) distribution of amphotericin B (AmpB) and amphotericin B lipid complex [ABLC; Abelcet composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG)] and define the relationship between LP lipid concentration and composition and the distribution of AmpB and ABLC in human plasma with varying total and lipoprotein cholesterol and triglycerides. AmpB and ABLC at a concentration of 20 microg amphotericin B/mL were incubated in plasma obtained from different human subjects (n = 7) for 60 min at 37 degrees C. Following these incubations plasma samples were separated into their high-density lipoprotein (HDL), triglyceride-rich lipoprotein (TRL; which contains very low-density lipoproteins and chylomicrons), low-density lipoprotein (LDL), and lipoprotein-deficient (LPDP) fractions by density-gradient ultracentrifugation (UC) and each fraction was assayed for AmpB using high-pressure liquid chromatography (HPLC). The HDL fraction was further separated into its HDL3 and HDL2 subclasses by UC and assayed for AmpB using HPLC. Separation of HDL into its subclasses was confirmed by gel electrophoresis. To assess the influence of modified lipoprotein concentrations and lipid composition on the plasma distribution of AmpB and ABLC, these compounds were incubated in plasmas from human subjects with varying total and lipoprotein lipid concentrations. In addition, to demonstrate that alterations in HDL lipid composition influence the plasma distribution of ABLC, ABLC (20 microg amphotericin B/mL) was incubated in plasma pretreated with dithionitrobenzoate (DTNB, a compound which inhibits lecithin:cholesterol acyltransferase conversion of HDL3 free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. Total plasma and lipoprotein cholesterol (TC), free cholesterol (fC), esterified cholesterol (CE), triglyceride (TG), phospholipid (PL), and protein (TP) concentrations in each human sample were determined by enzymatic assays. When AmpB was incubated in human plasmas of varying lipid concentrations, the majority of the drug was recovered in the LPDP fraction. However, the majority of AmpB was recovered in the HDL3 fraction following the incubation of ABLC. Differences in lipid coat content (fC and PL) carried by HDL influenced the distribution of ABLC within plasma of different human subjects. These findings were confirmed by the DTNB treatment experiments. These findings suggest that the association of AmpB with DMPC and DMPG to form drug-lipid complexes modifies the plasma distribution of the AmpB. In addition, the distribution of ABLC among plasma lipoproteins of different human subjects is defined by the HDL lipid coat content and is possibly an important consideration when evaluating the pharmacokinetics, toxicity, and activity of these compounds following administration to humans with differing plasma lipid concentrations.

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Section: Introductionmentioning

confidence: 99%

Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content

Kennedy

1999

Journal of Pharmaceutical Sciences

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“…The mechanism for brevetoxin uptake under these conditions is also consistent with the passive diffusion of cholesterol. Certain drugs show a preference for HDL among the lipoproteins; however, this may be due to the high protein:lipid ratio of HDL (Cassidy et al 1998; Kennedy and Wasan 1999; Wasan et al 1997). Further studies will be needed with brevetoxins to determine the degree of selectivity for the toxin to the different lipoprotein classes, with particular reference to lipoprotein profiles representative of human plasma.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Brevetoxin (PbTx-3) in Mouse Plasma: Association with High-Density Lipoproteins

Woofter

Spiess

Ramsdell

2005

Environ Health Perspect

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We investigated the brevetoxin congener PbTx-3 to determine its distribution among carrier proteins, including albumin and blood lipoproteins. Using a radiolabeled brevetoxin tracer (PbTx-3), we found that 39% of the radiolabel remained associated with components in mouse plasma after > 15 kDa cutoff dialysis. Of this portion, only 6.8% was bound to serum albumin. We also examined the binding of brevetoxin to various lipoprotein fractions. Plasma, either spiked with PbTx-3 or from mice treated for 30 min with PbTx-3, was fractionated into different-sized lipoproteins by iodixanol gradient ultracentrifugation. Each fraction was then characterized and quantified by agarose gel electrophoresis and brevetoxin radioimmunoassay, respectively. In both the in vitro and in vivo experiments, the majority of brevetoxin immunoreactivity was restricted to only those gradient fractions that contained high-density lipoproteins (HDLs). Independent confirmation of brevetoxin binding to HDLs was provided by high molecular weight (100 kDa cutoff) dialysis of [3H]PbTx-3 from lipoprotein fractions as well as a scintillation proximity assay using [3H]PbTx-3 and purified human HDLs. This information on the association of brevetoxins with HDLs provides a new foundation for understanding the process by which the toxin is delivered to and removed from tissues and may permit more effective therapeutic measures to treat intoxication from brevetoxins and the related ciguatoxins.

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“…These findings suggested that a different mechanism which was not influenced by the lipoprotein mass determined the plasma distribution of liposomal nystatin. Further studies are required for clarification of this issue [122,134].…”

Section: Plasma Distribution Of Liposomal Nystatin Differs From That mentioning

confidence: 97%

Lipid-based Antifungal Agents Current Status

Arıkan¹,

Rex

2001

CPD

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Immunocompromised patients are well known to be predisposed to developing invasive fungal infections. These infections are usually difficult to diagnose and more importantly, the resulting mortality rate is high. The limited number of antifungal agents available and their high rate of toxicity are the major factors complicating the issue. However, the development of lipid-based formulations of existing antifungal agents has opened a new era in antifungal therapy. The best examples are the lipid-based amphotericin B preparations, amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec or Amphocil), and liposomal amphotericin B (AmBisome). These formulations have shown that antifungal activity is maintained while toxicity is reduced. This progress is followed by the incorporation of nystatin into liposomes. Liposomal nystatin formulation is under development and studies of it have provided encouraging data. Finally, lipid-based formulations of hamycin, miconazole, and ketoconazole have been developed but remain experimental. Advances in technology of liposomes and other lipid formulations have provided promising new tools for management of fungal infections.

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Plasma Lipoprotein Distribution of Liposomal Nystatin Is Influenced by Protein Content of High-Density Lipoproteins

Cited by 29 publications

References 36 publications

Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content

Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content

Distribution of Brevetoxin (PbTx-3) in Mouse Plasma: Association with High-Density Lipoproteins

Lipid-based Antifungal Agents Current Status

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