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1.  Effects of disodium ascorbyl phytostanol phosphates (FM-VP4) on cholesterol accumulation within rat intestinal cells 
AAPS PharmSci  2003;5(1):55-61.
The objective of this study was to determine whether FM-VP4, a novel compound derived from plant sterols, can effectively reduce cholesterol accumulation within rat intestinal epithelial crypt (IEC-6) cells. IEC-6 cells were cultured in Dulbeccos minimal essential medium (DMEM) containing 5% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 0.1 units/mL insulin at 37°C under a humidified 5% CO2 atmosphere and seeded at 6.4×104 cells/well in 48-well plates. Experiments were initiated 14 days postconfluence. IEC-6 cells were exposed to [3H]cholesterol micelles (containing oleic and taurcholic acids), co-incubated with FM-VP4 (0, 10, 50, and 100 μM) in Hepes Buffered Sterile Saline (HBSS). Cells were also preincubated with FM-VP4 prior to [3H]cholesterol micelle incubation to determine whether its effects are elicited intracellularly. The cellular localization of cholesterol was determined using digitonin. To determine the effects of cholesterol on the extent of FM-VP4 accumulation within IEC-6 cells, [3H]FM-VP4 was incubated with IEC-6 cells in the presence of unlabeled cholesterol micelles (0, 10, and 50 μM). The extent of [3H]cholesterol or [3H]FM-VP4 associated with cell monolayers was determined after cell lysis using liquid scintillation counting in a Beckman LS6500 Scintillation Counter. Dose-response and time course studies were performed in which control (no FM-VP4 treatment) and FM-VP4 (10–100 μM) were co-incubated with 50-μM [3H]cholesterol micelles from 1 minute to 24 hours. Incubation with only 50-μM FM-VP4 for less than 24 hours resulted in a 50% to 60% reduction (n=6, P<.05) in [3H]cholesterol associated with the monolayer compared with control (n=6). Preincubation of FM-VP4 did not elicit a significant reduction in cholesterol accumulation compared with control (n=6). Approximately 25% of the total [3H]cholesterol associated with the cells was determined to be cytosolic, while 75% was noncytosolic in the presence and/or absence of FM-VP4. [3H]FM-VP4 was also shown to associate with IEC-6 cells at similar concentrations to cholesterol with the most pronounced inhibition of FM-VP4 accumulation occurring at a cholesterol concentration of 50 μM. However, cholesterol-induced inhibition was detectable only after 1 hour of incubation. FM-VP4 inhibits cholesterol accumulation within IEC-6 cells and is most effective at equimolar concentrations with cholesterol. Our findings further suggest that the action of FM-VP4 is likely at the cell surface and not elicited intracellularly.
PMCID: PMC2751474  PMID: 12713278
IEC-6 cells; phytostanols; cholesterol accumulation; cytotoxicity
2.  Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: Studies with cyclosporine A 
AAPS PharmSci  2002;4(4):95-101.
Lipoproteins are a heterogeneous population of macromolecular aggregates of lipids and proteins that are responsible for the transport of lipids through the vascular and extravascular fluids from their site of synthesis or absorption to peripheral tissues. Lipoproteins are involved in other biological processes as well, including coagulation and tissue repair, and serve as carriers of a number of hydrophobic compounds within the systemic circulation. It has been well documented that disease states (eg, AIDS, diabetes, cancer) significantly influence circulating lipoprotein content and composition. Therefore, it appears possible that changes in the lipoprotein profile would affect not only the ability of a compound to associate with lipoproteins but also the distribution of the compound within the lipoprotein subclasses. Such an effect could alter the pharmacokinetics and pharmacological action of the drug. This paper reviews the factors that influence the interaction of one model hydrophobic compound, cyclosporine A, with lipoproteins and the implications of altered plasma lipoprotein concentrations on the pharmacological behavior of this compound.
PMCID: PMC2751319  PMID: 12646002

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