title: The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.
abstract: We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg. kg-1. d-1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (d<1.006 g/mL; Sf>20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; P<0.01). The TRL triglyceride 0- to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0- to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; P=0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (r=-0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.
authors.affiliation: Department of Medicine and The John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: J R
authors.initials: JR
authors.lastname: Burnett
authors.forename: P H
authors.initials: PH
authors.lastname: Barrett
authors.forename: P
authors.initials: P
authors.lastname: Vicini
authors.forename: D B
authors.initials: DB
authors.lastname: Miller
authors.forename: D E
authors.initials: DE
authors.lastname: Telford
authors.forename: S J
authors.initials: SJ
authors.lastname: Kleinstiver
authors.forename: M W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002914:Chylomicrons / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008657:Metabolic Clearance Rate; D019518:Postprandial Period; D011758:Pyrroles / Q000494:pharmacology*; D011973:Receptors, LDL / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D002914:Chylomicrons; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D011973:Receptors, LDL; D014280:Triglycerides; D000069059:Atorvastatin