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 [(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.
Wasan
K M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Avenue, Vancouver, British Columbia, Canada V6T 1Z3. kwasan@interchange.ubc.ca
Holtorf
L
L
Subramanian
R
R
Cassidy
S M
SM
Pritchard
P H
PH
Stewart
D J
DJ
Novak
E
E
Moghadasian
M H
MH
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005215:Fasting; D007408:Intestinal Absorption; D008297:Male; D010840:Phytosterols / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012855:Sitosterols / Q000008:administration & dosage / Q000494:pharmacology*; D014316:Tritium
D000924:Anticholesteremic Agents; D010840:Phytosterols; D012855:Sitosterols; D014316:Tritium; C003535:campestanol; D002784:Cholesterol; C021255:stigmastanol