The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs

We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzy me A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (a poB) secretion into plasma. To test the hypothesis that atorvastatin modula tes exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an or al fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given t o 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 b y use of SAAM II and kinetic analysis performed on the plasma retinyl palmi tate (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 treatm ent 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-f old (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 fr actional clearance rate was negatively correlated with very low density lip oprotein apoB production rate measured in the fasting state (r=-0.49). Thus , although atorvastatin had no effect on intestinal TRL assembly and secret ion, plasma TRL clearance was significantly increased an effect that may re late to a decreased competition for removal processes by hepatic very low d ensity lipoprotein.