Effect of YM‐53601, a novel squalene synthase inhibitor, on the clearance rate of plasma LDL and VLDL in hamsters

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. 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. 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. 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. British Journal of Pharmacology (2002) 137, 561–567. doi:10.1038/sj.bjp.0704906