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 hyperchole sterolemia (EH) due both to an increased low density lipoprotein (LDL) synthetic rate and decreased LDL receptor activity. Pre-established E H in this model was used to assess the ability and mechanism by which atorvastatin lowers total plasma cholesterol (TPC) compared to the ref erence agent lovastatin. Rabbits were fed a casein diet for 6 weeks, o btaining average TPC levels above 200 mg/dl. To ensure equivalent mean cholesterol concentrations, animals were randomized into treatment gr oups based on the 6-week TPC levels, and fed the casein diet alone or in combination with either atorvastatin or lovastatin for an additiona l 6 weeks. Under these conditions, new steady-state cholesterol values were established. Lipoprotein concentrations and distributions were d etermined at this point. Compared to pretreatment values, TPC were sim ilar in untreated animals. Atorvastatin, however, significantly reduce d TPC by 38%, 45%, and 54% at the 1, 3, and 10 mg/kg doses, respective ly. Statistically significant lowering of TPC (35%) by lovastatin was only achieved at the 10 mg/kg dose. To determine the mechanism by whic h atorvastatin lowered TPC in the EH rabbits, kinetic studies using hu man [I-125]-LDL were performed in a subset of animals maintained on th e casein diet alone (n = 5), or those treated with 3 mg/kg of atorvast atin (n = 5) or lovastatin (n = 7). In this set of studies, atorvastat in significantly lowered TPC compared to control and lovastatin-treate d rabbits by 57% and 46%, respectively. Lovastatin treatment resulted in a 20% decrease in TPC as compared to untreated controls. The LDL fr actional catabolic rates (FCR) were similar for all groups (0.06-0.07 pools/hour). LDL production rates (PR), however, were significantly le ss in the atorvastatin-treated rabbits than either the control or lova statin 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 i n a diminished apolipoprotein (ape) B pool size (16.8 +/- 2.0 mg/kg) a s compared to either control (40.4 +/- 3.7 mg/kg) or lovastatin-treate d (28.4 +/- 3.4 mg/kg) groups. The LDL PR with lovastatin treatment wa s 20% lower than that of the control group, though this value did not reach statistical significance, whereas the apo B mass was significant ly reduced by 30%. These studies demonstrate that 3-hydroxy-3-methylgl utaryl-co-enzyme A (HMG-CoA) reductase inhibitors can reverse the diet -induced hypercholesterolemia in the EH rabbit model. The underlying m echanism of this reversal is a decrease in the apparent LDL production rate. At equivalent doses, atorvastatin is more efficacious in this m odel than lovastatin.