All of the in vivo data described thus far involve animals fed diets that are substantially higher in fat and cholesterol than the animals' normal chow diet. Despite the substantial activity of ezetimibe and other azetidinone CAIs in these models, none of the compounds tested significantly reduced plasma cholesterol levels in animals fed a normal chow diet. While this was initially a concern, this observation ultimately led to one of the most important aspects of the profile of ezetimibe. In considering the possible reasons for the lack of substantial effect on serum cholesterol in the absence of a high cholesterol diet, Davis reasoned that a CAI might stimulate hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity. This could compensate for a reduced cholesterol load due to inhibition of intestinal cholesterol absorption. If this were the case, then coadministration of a CAI and an HMG-CoA reductase inhibitor should produce an enhanced reduction in serum cholesterol at doses that were less effective or ineffective as monotherapy. To test this hypothesis, Davis etal.administered ezetimibe (0.007 mgkg_ 1) or lovastatin (5 mgkg_ 1) to chow-fed dogs over 14 days.39 While neither compound had a substantial effect on serum cholesterol alone, the combination produced a profound reduction in serum cholesterol (Figure 23).
Similar experiments demonstrated a comparable effect in other species and with other statins. These data suggested that ezetimibe would be effective at reducing cholesterol levels in humans and would be particularly effective in combination HMG-CoA reductase inhibitors.
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