Assessing plasma pharmacokinetics of cholesterol following oral coadministration with a novel vegetable stanol mixture to fasting rats

The purpose of this project was to assess the plasma pharmacokinetics of [H -3]cholesterol following coadministration of a novel vegetable stanol mixtu re composed of sitostanol and campestanol (FCP-3P4) to fasting rats. Follow ing 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-do se oral gavage at 0700 h of either: [H-3] cholesterol (25 mu Ci/mL), FCP-3P 4 (5 mg/kg) + [H-3]cholesterol (25 mu Ci/mL), FCP-3P4 (12.5 mg/kg) + [H-3]c holesterol (25 mu Ci/mL), FCP-3P4 (25 mg/kg) + [H-3]cholesterol (25 mu Ci/m L), FCP-3P4 (50 mg/kg) + [H-3]cholesterol (25 mu Ci/mL), or FCP-3P4 (1.00 m g/kg) + [H-3]cholesterol (25 mu Ci/mL). Intralipid(R) (10%) was the vehicle used to solubilize and coadminister [H-3]cholesterol and FCP-3P4. Liquid c hromatography-mass spectrometry analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid(R). Analysis of plasma pharm acokinetics 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. Plasm a samples were obtained by centrifugation of the blood samples and analyzed for [H-3]cholesterol radioactivity. Pharmacokinetics analysis was performe d by standard noncompartmental methods using statistical moment theory. Thi n-layer chromatography was used to confirm that the majority of radioactivi ty measured in plasma was cholesterol (in the form of esterified or unester ified cholesterol). Greater than 90% of the radioactivity measured in all p lasma 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 [H-3]cholesterol concentration versu s time from 0 to 48 h (AUC(0-48h)) and maximum concentration (C-max) in a d ose-dependent manner. However, coadministration of FCP-3P4 at 25, 50, and 1 00 mg/kg resulted in a significant increase in apparent total body clearanc e (CL/F, where F is the bioavailability constant), apparent volume of distr ibution (V-d/F), and oral absorption rate constant (k(a)) of [H-3]cholester ol compared with controls. These findings suggest that the novel vegetable stanol mixture, FCP-3P4, modifies the plasma pharmacokinetics of [H-3]chole sterol in fasting rats on oral coadministration. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.