Effect of simvastatin on receptor mediated metabolism of low density lipoprotein in guinea pigs

Abstract This study examined the effects of simvastatin, an inhibitor of HMG-CoA reductase, on the metabolism of labelled human low density lipoprotein (LDL) in animal models. Administration of 10 mg/kg per day simvastatin for 2 weeks reduced the levels of total cholesterol, LDL-cholesterol and triglycerides by 5.7 mg/dl (16%), 8.8 mg/dl (36%) and 4.9 mg/dl (13%), respectively in guinea pigs. High density lipoprotein-cholesterol levels rose 0.8 mg/dl (29%) by simvastatin treatment. Measurements of turnover of LDL were determined between simvastatin-treated guinea pigs and untreated guinea pigs using intravenous injection of 131 I-labelled LDL and 125 I-labelled galactose-treated LDL to quantify the LDL receptor pathway. Simvastatin significantly increased the fractional catabolic rate (FCR) of the LDL receptor-dependent pathway. In contrast, the FCR of the LDL receptor-independent pathway was not altered by simvastatin therapy. The FCR for LDL isolated from simvastatin-treated subjects compared to that from control subjects was very similar in both control and simvastatin-fed guinea pigs. These findings suggest that simvastatin mainly reduced serum cholesterol levels by accelerated FCR of LDL receptor mediated pathway.