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Plasma lipoprotein distribution of amphotericin B formulations : potential role of phospholipid transfer protein Patankar, Nilesh A.

Abstract

The objectives of this study were to compare the plasma distribution profile of Amphotericin B (AmpB) following incubation of three commonly used formulations, Fungizone®, Abelcet® and Ambisome® and to determine if phospholipid transfer protein (PLTP) facilitates the transfer of AmpB into high density lipoproteins (HDL) following incubation of AmpB-phospholipid complex within human plasma. Methods: Plasma lipoprotein distribution of AmpB was studied following incubation of Fungizone®, Abelcet® and Ambisome® at an AmpB concentration of 20 pg1mL within human plasma at 37OC for a range of incubation times. These plasmas were subsequently fractionated into their lipoprotein and lipoprotein deficient fractions by gradient density ultracentrifugation. Each fraction was analyzed for AmpB by high performance liquid chromatography (HPLC). Plasma phospholipid transfer protein (PLTP) assay was established and characterized in vitro using a commercially available kit. Plasma samples from six individual donors were analyzed for PLTP activity. PLTP activity observed from plasmas was then plotted against the percentage of AmpB recovered from the HDL fractions of the respective plasmas. HDL fractions of the same six plasmas were analyzed for the phospholipid content. HDL-phospholipid content was plotted against the percentage of AmpB recovered from the HDL fractions. In order to inhibit plasma PLTP activity, three different approaches were used. 1. Incubation of plasma with polyclonal antibody to PLTP. 2. Incubation of plasma with thimerosal. 3. Heating of plasma at 56°C for 1 hour. Results: Following incubation of Fungizone®, within human plasma, the majority (- 50-60%) of the incubated AmpB was recovered from the lipoprotein deficient fraction (LPDP). However, following incubation of lipid based formulations (i.e. Abelcet® and Ambisome® ), the majority (- 60-85%) of incubated AmpB was recovered from the HDL fraction. Plasmas containing elevated total cholesterol (TC) and triglycerides (TG) levels (plasmas with TC and TG >200 mg/dL) showed a four-fold higher AmpB-LDL association than plasmas with TC and TG levels

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