Development of novel water-soluble phytostanol analogs: disodium ascorbyl phytostanyl phosphates (FM-VP4): preclinical pharmacology, pharmacokinetics and toxicology.
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.
Ng
Agatha W K
AW
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada.
Lukic
Tatjana
T
Pritchard
P Haydn
PH
Wasan
Kishor M
KM
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000188:drug therapy / Q000473:pathology; D018938:Caco-2 Cells; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010840:Phytosterols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; C445524:FM-VP4 compound; D000960:Hypolipidemic Agents; D010840:Phytosterols; D014280:Triglycerides; D002784:Cholesterol