COMPARATIVE EFFECTS OF HMG-COA REDUCTASE INHIBITORS ON APO-B PRODUCTION IN THE CASEIN-FED RABBIT - ATORVASTATIN VERSUS LOVASTATIN

Rabbits fed a diet enriched in casein develop an endogenous hypercholesterolemia (EH) due both to an increased low density lipoprotein (LDL) synthetic rate and decreased LDL receptor activity. Pre-established EH in this model was used to assess the ability and mechanism by which atorvastatin lowers total plasma cholesterol (TPC) compared to the reference agent lovastatin. Rabbits were fed a casein diet for 6 weeks, obtaining average TPC levels above 200 mg/dl. To ensure equivalent mean cholesterol concentrations, animals were randomized into treatment groups based on the 6-week TPC levels, and fed the casein diet alone or in combination with either atorvastatin or lovastatin for an additional 6 weeks. Under these conditions, new steady-state cholesterol values were established. Lipoprotein concentrations and distributions were determined at this point. Compared to pretreatment values, TPC were similar in untreated animals. Atorvastatin, however, significantly reduced TPC by 38%, 45%, and 54% at the 1, 3, and 10 mg/kg doses, respectively. Statistically significant lowering of TPC (35%) by lovastatin was only achieved at the 10 mg/kg dose. To determine the mechanism by which atorvastatin lowered TPC in the EH rabbits, kinetic studies using human [I-125]-LDL were performed in a subset of animals maintained on the casein diet alone (n = 5), or those treated with 3 mg/kg of atorvastatin (n = 5) or lovastatin (n = 7). In this set of studies, atorvastatin significantly lowered TPC compared to control and lovastatin-treated rabbits by 57% and 46%, respectively. Lovastatin treatment resulted in a 20% decrease in TPC as compared to untreated controls. The LDL fractional catabolic rates (FCR) were similar for all groups (0.06-0.07 pools/hour). LDL production rates (PR), however, were significantly less in the atorvastatin-treated rabbits than either the control or lovastatin groups (1.0 +/- 0.1 vs. 2.2 +/- 0.3 and 1.8 +/- 0.3 mg/kg/hour, respectively). The atorvastatin-induced decrease in LDL PR resulted in a diminished apolipoprotein (ape) B pool size (16.8 +/- 2.0 mg/kg) as compared to either control (40.4 +/- 3.7 mg/kg) or lovastatin-treated (28.4 +/- 3.4 mg/kg) groups. The LDL PR with lovastatin treatment was 20% lower than that of the control group, though this value did not reach statistical significance, whereas the apo B mass was significantly reduced by 30%. These studies demonstrate that 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitors can reverse the diet-induced hypercholesterolemia in the EH rabbit model. The underlying mechanism of this reversal is a decrease in the apparent LDL production rate. At equivalent doses, atorvastatin is more efficacious in this model than lovastatin.