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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1906-1914.)
© 1998 American Heart Association, Inc.

Original Contributions

The HMG-CoA Reductase Inhibitor Atorvastatin Increases the Fractional Clearance Rate of Postprandial Triglyceride-Rich Lipoproteins in Miniature Pigs

John R. Burnett; P. Hugh R. Barrett; Paolo Vicini; David B. Miller; Dawn E. Telford; Sandra J. Kleinstiver; Murray W. Huff

From the Department of Medicine and The John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada (J.R.B., D.B.M., D.E.T, S.J.K., M.W.H.), and the Departments of Bioengineering and Medicine, University of Washington, Seattle (P.H.R.B., P.V.).

Correspondence to Murray W. Huff, The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Dr, London, Ontario N6A 5K8, Canada. E-mail mhuff{at}julian.uwo.ca

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; S_f>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.

Key Words: HMG-CoA reductase inhibitor • atorvastatin • triglyceride-rich lipoproteins • tracer kinetics • compartmental model

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