| Abstract: | ![]()
FM‐VP4 is a novel inhibitor of cholesterol absorption that has lipid lowering and body weight reducing properties. In vitro and in vivo studies were performed to investigate the lipid‐lowering effects, mechanism of action, pharmacokinetics, and toxicity of FM‐VP4. FM‐VP4 decreased cholesterol accumulation in Caco‐2 cells by approximately 50%; its activity appeared to be independent of pancreatic lipase, p‐glycoprotein, or cholesterol incorporation in micelles. In animal studies, FM‐VP4 was added to the diet or drinking water and the following results were obtained. In gerbils 2% FM‐VP4 produced mean 56 and 53% reduction in total cholesterol (TC) after 4 and 8 weeks, respectively. This reduction was entirely due to the loss of the low‐density lipoprotein (LDL) pool, which was reduced to undetectable levels at either time point. At 8 weeks, high‐density lipoprotein (HDL) concentration had risen by a mean of 34% whereas total triglyceride (TG) concentrations had decreased by a mean of 60%. FM‐VP4 also had a profound effect on body weight in these animals. At 8 weeks, the mean body weight was in the 4% FM‐VP4 treatment group 25% lower than in the control group. No hepatic or renal toxicity was associated with these changes. In Apo E‐deficient mice, after 4‐ and 8‐week treatments FM‐VP4 caused a significant decrease in both TC and TG concentrations compared to controls. After 12 weeks, the areas of atherosclerotic lesion involvement in the aortic roots were decreased by a mean of 80% in the 0.5, 1, and 2% FM‐VP4 treatment groups compared to controls. Taken together, these results suggest that FM‐VP4 is a potential new drug with lipid‐lowering and weight loss potential, without apparent toxicity. |
