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The purpose of this project was to assess the plasma pharmacokinetics of [(3)H]cholesterol following coadministration of a novel vegetable stanol mixture composed of sitostanol and campestanol (FCP-3P4) to fasting rats. Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six treatment groups and received a single-dose oral gavage at 0700 h of either: [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (12.5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (25 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (50 mg/kg) + [(3)H]cholesterol (25 microCi/mL), or FCP-3P4 (100 mg/kg) + [(3)H]cholesterol (25 microCi/mL). Intralipid (10%) was the vehicle used to solubilize and coadminister [(3)H]cholesterol and FCP-3P4. Liquid chromatography-mass spectrometry analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid. Analysis of plasma pharmacokinetics was initiated by sampling 0.5 mL of blood prior to and 0.25, 0.5 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24, 28, 32, and 48 h post-oral gavage. Plasma samples were obtained by centrifugation of the blood samples and analyzed for [(3)H]cholesterol radioactivity. Pharmacokinetics analysis was performed by standard noncompartmental methods using statistical moment theory. Thin-layer chromatography was used to confirm that the majority of radioactivity measured in plasma was cholesterol (in the form of esterified or unesterified cholesterol). Greater than 90% of the radioactivity measured in all plasma samples was cholesterol-associated (in the form of either esterified or unesterified cholesterol). The coadministration of FCP-3P4 significantly decreased the area under the curve of [(3)H]cholesterol concentration versus time from 0 to 48 h (AUC(0-48h)) and maximum concentration (C(max)) in a dose-dependent manner. However, coadministration of FCP-3P4 at 25, 50, and 100 mg/kg resulted in a significant increase in apparent total body clearance (CL/F, where F is the bioavailability constant), apparent volume of distribution (V(d)/F), and oral absorption rate constant (k(a)) of [(3)H]cholesterol compared with controls. These findings suggest that the novel vegetable stanol mixture, FCP-3P4, modifies the plasma pharmacokinetics of [(3)H]cholesterol in fasting rats on oral coadministration.

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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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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.

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The plasma lipoprotein distribution of free nystatin (Nys) and liposomal nystatin (L-Nys) in human plasma samples with various lipoprotein lipid and protein concentrations and compositions was investigated. To assess the lipoprotein distributions of Nys and L-Nys, human plasma was incubated with Nys and L-Nys (equivalent to 20 microg/ml) for 5 min at 37 degreesC. The plasma was subsequently partitioned into its lipoprotein and lipoprotein-deficient plasma fractions by step-gradient ultracentrifugation, and each fraction was analyzed for Nys content by high-pressure liquid chromatography. The lipid and protein contents and compositions of each fraction were determined with enzymatic kits. Following the incubation of Nys and L-Nys in human plasma the majority of Nys recovered within the lipoprotein fractions was recovered from the high-density lipoprotein (HDL) fraction. Incorporation of Nys into liposomes consisting of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol significantly increased the percentage of drug recovered within the HDL fraction. Furthermore, it was observed that as the amount of HDL protein decreased the amounts of Nys and L-Nys recovered within this fraction decreased. These findings suggest that the preferential distribution of Nys and L-Nys into plasma HDL may be a function of the HDL protein concentration.

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The plasma lipoprotein distribution of potential drug candidates is not commonly studied. For some hydrophobic drug candidates, attainment of similar plasma free drug levels has not been associated with uniform production of pharmacological activity in different animal species. It is well-known that plasma lipoprotein lipid profiles vary considerably between different animal species. In addition, human disease states can significantly influence plasma lipoprotein profiles, resulting in altered therapeutic outcomes. Current research has shown that lipoprotein binding of drug compounds can significantly influence not only the pharmacological and pharmacokinetic properties of the drug, but the relative toxicity as well. Elucidation of drug distribution among plasma lipoproteins is expected to yield valuable insight into factors governing the pharmacological activity and potential toxicity of the drug. This paper will present an historical perspective and summarize the latest research in the area of lipoprotein-drug interactions.

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The physical characteristics and lipoprotein distribution of free nystatin (NYS) and liposomal NYS (L-NYS) in human plasma were investigated. To determine the percentage of NYS that was lipid associated following incubation in human plasma, C18 reverse-phase extraction columns were used. To assess plasma drug distribution, NYS and L-NYS (20 microg/ml) were incubated in human plasma for 5, 60, and 120 min at 37 degrees C. After each interval, plasma was removed and separated into its lipoprotein and lipoprotein-deficient plasma (LPDP) fractions by ultracentrifugation and assayed for NYS by high-pressure liquid chromatography. Further studies evaluated the liposome structure of L-NYS by filtering through a 0.14-microm-pore-size microfilter before and after the addition of human plasma. When reconstituted L-NYS (mean particle diameter +/- standard deviation, 321 +/- 192 nm) was applied to a C18 column, 67% +/- 4% of the initial NYS concentration was associated with the lipid. When plasma samples containing L-NYS that had been incubated for 5 to 120 min at 37 degrees C were applied to C18 columns, 66 to 76% of the NYS was lipid associated. Incubation of NYS in human plasma for 5 min at 37 degrees C resulted in 3% +/- 1% of the initial NYS concentration incubated in the low-density lipoprotein (LDL) fraction, 23% +/- 4% of that in the high-density lipoprotein (HDL) fraction, and 66% +/- 10% of that in the LPDP fraction. In contrast, the distribution of NYS following incubation of L-NYS in human plasma for 5 min was 13% +/- 2% in the LDL fraction, 44% +/- 5% in the HDL fraction, and 42% +/- 5% in the LPDP fraction. Similar results were observed following 60 and 120 min of incubation. In addition, the liposome structure of L-NYS was quickly lost when mixed with plasma. These findings suggest that rapid disruption of the L-NYS structure upon incubation in human plasma is consistent with its rapid distribution in plasma. The preferential distribution of NYS into the HDL fraction upon incubation of L-NYS may be a function of its phospholipid composition.

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Recent studies have shown that changes in lipoprotein cholesterol and triglyceride concentration alters the plasma distribution of free (Ann.) and liposomal annamycin (LAnn) and that the majority of Ann. is associated with high-density lipoproteins (HDL) following the incubation in plasma of LAnn. To demonstrate that alterations in HDL lipid composition and HDL structure may influence the plasma distribution of Ann. and LAnn, Ann. and LAnn (20 micrograms/mL) were incubated in plasma pretreated with dithionitrobenzoate (DTNB, a compound which inhibits the conversion of free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. In addition, Ann. and LAnn were co-incubated with DTNB in plasma for 60 min at 37 degrees C. Following incubation the plasma was separated into its HDL, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and lipoprotein-deficient plasma (LPDP) fractions by ultracentrifugation and assayed for Ann. by fluorimetry. The HDL plasma cholesterol:triglyceride concentration ratio was significantly decreased following 18 h of DTNB pretreatment compared to untreated plasma controls. No significant differences in LDL/VLDL plasma cholesterol:triglyceride concentration ratio following 18 h of DTNB pretreatment was observed. An increased number of discoidal HDL particles were observed following 18 h of DTNB pretreatment. When Ann. was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL, LDL, and VLDL fractions significantly increased. However, the percentage of Ann. recovered within the LPDP fraction was significantly decreased. When LAnn was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL fraction significantly decreased. The percentage of Ann. recovered in the LPDP fraction significantly increased when LAnn was incubated in plasma pretreated with DTNB for 18 h. No significant differences in Ann. lipoprotein distribution were observed when Ann. and LAnn were co-incubated with DTNB in plasma for 1 h. These findings suggest that the cholesterol:triglyceride concentration ratio and physical structure of HDL maybe important in defining the capacity of HDL to sequester Ann.

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To obtain objective information about binge- and non-binge-eating behavior, 12 women with bulimia and ten women without eating problems (controls) were asked to eat four meals in a structured laboratory setting, on separate nonconsecutive days. The same instructions were given to both groups. On two days, they were asked to eat a normal amount, and on two days, they were asked to eat as much as they could, ie, to binge. For each type of instruction, they were given a single- and a multiple-course meal. The patients ate significantly more than the controls when asked to binge, both on the multiple-course meals that they rated as typical of binges and on the single-course meals. When they were asked to eat normally, there was no significant difference in intake between patients and controls on either single- or multiple-course meals. After all meals, hunger ratings of patients were significantly higher than hunger ratings of controls. There was also a significant positive correlation between intakes of single- and multiple-course binge meals and an inverse correlation between intake of multiple-course binge meals in bulimic patients and their rating of how well they controlled their eating. Thus, a structured laboratory eating situation can be used to reveal differences between bulimic and normal individuals and has the potential for assessing clinical status and exploring mechanisms responsible for binge eating.

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This report describes a standard procedure for studying the disordered eating behavior of bulimic patients in a laboratory setting. Test meals were given to eight normal weight women with bulimia under four different conditions on non-consecutive days. On day 1 they were asked to consume as much as they "would normally eat" by means of a straw from an opaque container holding 1500 g of a palatable liquid food. An eating monitor recorded the pattern of consumption. Five patients showed abnormalities of either excessive eating or acceleration of the rate of eating. On the second and third days they were given standardized amounts of an array of foods. They were instructed to eat normally on one of these days and to eat as much as they could on the other, in counterbalanced order. All patients ate to excess when they were asked, over a 28 to 90 min period, and consumed a mean of 4477 kcal (range 2083-8499 kcal) with a macronutrient composition similar to that of the typical American diet. They all vomited afterwards. On the day they were asked to eat normally, five patients overate and vomited, two ate very little, and one refused to participate. On the fourth day patients were asked to eat as much as they could of a single item, ice cream. Six patients consumed a mean of 1545 kcal (range 741-2919 kcal); one patient ate only 85 kcal; and one patient refused to participate. There were large and significant correlations among the sizes of the various meals consumed in excess.(ABSTRACT TRUNCATED AT 250 WORDS)

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