title: Effect of YM-53601, a novel squalene synthase inhibitor, on the clearance rate of plasma LDL and VLDL in hamsters.
abstract: 1. To better understand how it decreases plasma cholesterol and triglyceride, we evaluated the effect of YM-53601 ((E-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbozole monohydrochloride) on the clearance rate of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) in hamsters. 2. Treatment with YM-53601 at 50 mg kg(-1) for 5 days in hamsters fed a normal diet enhanced the disappearance of 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-VLDL and DiI-LDL. This effect on DiI-LDL was lost in the early phase after DiI-methyl(met)-LDL, chemically modified to block LDL receptor binding, was injected in hamsters, but was retained in the late phase. Pre-treatment with protamine sulphate, which inhibits the activity of LPL, also failed to enhance DiI-VLDL clearance rate by YM-53601. 3. Even on single oral administration at 30 mg kg(-1), YM-53601 enhanced the disappearance of the high concentration of plasma triglyceride after injection of intrafat, an emulsion of fat. Plasma triglyceride was significantly decreased as soon as 1 h after single administration of YM-53601 in hamsters fed a normal diet. 4. These results indicate that the decrease in plasma total cholesterol and triglyceride after the treatment with YM-53601 is due to its enhancement of the clearance rate of LDL and VLDL, respectively. Moreover, YM-53601 may be effective in decreasing plasma triglyceride levels early in the course of treatment of hypertriglyceridaemia in humans.
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood*; D015243:Cholesterol, VLDL / Q000097:blood*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D011812:Quinuclidines / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004791:Enzyme Inhibitors; D011812:Quinuclidines; C414830:YM 53601; D013186:Farnesyl-Diphosphate Farnesyltransferase