The purpose of this study was to determine if a relationship exists among total serum and lipoprotein cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the serum pharmacokinetics of AmpB in hypercholesterolemic rabbits administered AmpB and AmpB lipid complex (ABLC). After 10 days of cholesterol-enriched diet (0.50% [wt/vol]) or regular rabbit diet (control), each rabbit was administered a single intravenous bolus of AmpB or ABLC (1.0 mg/kg of body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, kidney toxicity, and serum lipoprotein distribution. Rabbits were humanely sacrificed after all blood samples were obtained, and tissues were harvested for drug analysis. Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total serum cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with levels in rabbits on a regular diet. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered AmpB. However, the magnitude of this increase was 2.5-fold greater in cholesterol-fed rabbits than in regular diet-fed rabbits. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered ABLC. Whereas AmpB pharmacokinetics were significantly altered in cholesterol-fed rabbits administered free AmpB, similar AmpB pharmacokinetics were observed in both rabbit groups administered ABLC. Renal AmpB levels were significantly increased in cholesterol-fed rabbits administered AmpB compared with those in all other groups. Hepatic and lung AmpB levels were elevated in cholesterol-fed rabbits administered free AmpB compared to controls. In addition, hepatic, lung, and spleen AmpB levels were significantly decreased in cholesterol-fed rabbits administered ABLC compared to controls. An increased percentage of AmpB was recovered in LDL–very-low-density lipoprotein fraction when free AmpB was administered to cholesterol-fed rabbits compared with those in all other groups. These findings suggest that increases in cholesterol, specifically, LDL cholesterol levels, modify the disposition and renal toxicity of free AmpB. However, the pharmacokinetics and renal toxicity of ABLC were independent of elevations in total and LDL cholesterol levels.

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.

The purpose of the present study was to determine if a relationship exists between the plasma cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the pharmacokinetics of AmpB in plasma in hypercholesterolemic rabbits administered multiple doses of amphotericin B (AmB) deoxycholate (Doc-AmB) and AmB lipid complex (ABLC). After 7 days of administration of a cholesterolenriched diet (0.50% [wt/vol]) or a regular rabbit diet, each rabbit was administered a single intravenous bolus of Doc-AmB (n ‫؍‬ 8) or ABLC (n ‫؍‬ 10) (1.0 mg/kg of body weight) daily for 7 consecutive days (a total of eight doses). Blood samples were obtained daily before and 24 h after the administration of each dose and serially thereafter following the administration of the last dose for the assessment of pharmacokinetics in plasma, kidney toxicity, plasma lipoprotein levels, and drug distribution in tissue. The pharmacokinetics of AmB in blood following the administration of ABLC were also determined in rabbits fed cholesterol-enriched and regular diets (n ‫؍‬ 3 each group). Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total, low-density lipoprotein (LDL), and triglyceride-rich lipoprotein (TRL) cholesterol levels in plasma compared with the levels in rabbits on a regular diet. No significant differences in total plasma triglyceride levels were observed. Significant increases in plasma creatinine levels were observed in rabbits fed a cholesterol-enriched diet (P < 0.05) and rabbits fed a regular diet (P < 0.05) when administered AmB. However, the magnitude of this increase was twofold greater in rabbits fed a regular diet than in rabbits fed a cholesterol-enriched diet. An increase in plasma creatinine levels was observed only in rabbits on a cholesterol-enriched diet administered ABLC. The pharmacokinetics of AmB were significantly altered in rabbits on a cholesterol-enriched diet administered Doc-AmB or ABLC compared to those in rabbits on a regular diet administered each of these compounds. The pharmacokinetics of AmB in blood were significantly different following ABLC administration but not following Doc-AmB administration in both rabbits fed cholesterolenriched diets and rabbits fed regular diets compared to their corresponding pharmacokinetics in plasma. An increased percentage of AmB was recovered in the TRL fraction when Doc-AmB was administered to rabbits fed a cholesterol-enriched diet than when it was administered to rabbits fed a regular diet. Furthermore, an increased percentage of AmB was recovered in the LDL and TRL fractions when ABLC was administered to rabbits fed a cholesterol-enriched diet rabbits fed a regular diet. These findings suggest that an increase in plasma cholesterol levels modifies the pharmacokinetics of AmB and renal toxicity following the administration of multiple intravenous doses of Doc-AmB and ABLC.Disseminated fungal infections such as candidiasis, histoplasmosis, and aspergillosis are on the rise, particularly in patients with ...

Plasma lipoproteins are a heterogeneous population of soluble, macromolecular aggregates of lipids and proteins. They are responsible for the transport of waterinsoluble nutrients through the vascular and extravascular fluids from their site of synthesis or absorption to peripheral tissues (1,2). These hydrophobic nutrients (triacylglycerols [TGs] and cholesteryl esters [CEs]) are delivered from the liver and intestine to other tissues in the body for storage or catabolism in the production of energy. Lipoproteins are also known to be involved in other biological processes, including coagulation and tissue repair as well as immune reactions (3,4).

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