title: The ACAT inhibitor avasimibe increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.
abstract: Previously, we have shown, in vivo, that the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe decreases hepatic apolipoprotein (apo) B secretion into plasma. To test the hypothesis that avasimibe modulates postprandial triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg) containing retinol was given to 9 control miniature pigs and to 9 animals after 28 days treatment with avasimibe (10 mg/kg/day, n=5; 25 mg/kg/day, n=4). The kinetic parameters for plasma retinyl palmitate (RP) metabolism were determined by multi-compartmental modeling using SAAM II. Avasimibe decreased the 2-h TRL (d<1.006 g/mL; S(f)>20) triglyceride concentrations by 34%. The TRL triglyceride 0-12 h area under the curve (AUC) was decreased by 21%. In contrast, avasimibe had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma, however, the TRL RP 0-12 h AUC was decreased by 17%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate (FCR) was increased 1.4-fold with avasimibe. The TRL RP FCR was negatively correlated with very low density lipoprotein (VLDL) apoB production rate measured in the fasting state (r=-0.504). No significant changes in total intestinal lipid concentrations were observed. Thus, although avasimibe had no effect on intestinal TRL secretion, plasma TRL clearance was significantly increased; an effect that may relate to a decreased competition with hepatic VLDL for removal processes.
authors.affiliation: Department of Core Clinical Pathology and Biochemistry, Pathwest Laboratory Medicine WA, Royal Perth Hospital and School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000081:Acetamides; D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D019518:Postprandial Period; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D014280:Triglycerides / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000081:Acetamides; D000085:Acetates; D004791:Enzyme Inhibitors; D008055:Lipids; D008074:Lipoproteins; D013449:Sulfonamides; D013451:Sulfonic Acids; D014280:Triglycerides; C423185:avasimibe; D002785:Sterol O-Acyltransferase