Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug.

摘要: The biosynthesis of cholesterol is mainly regulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Because the liver major site synthesis, it primary target class drugs known as HMG-CoA reductase inhibitors. Simvastatin (SV) a lactone prodrug which undergoes reversible metabolism. In hydroxy acid form (SVA) potent inhibitor SV well absorbed rats, dogs, and humans. After an oral dose SV, tissue distribution studies were consistent with high hepatic extraction relatively poor penetration SVA. majority radioactive eliminated in bile. portal/systemic gradient for 6'-OH-SVA, active biliary metabolite, suggests its probable reentry indicates potential prolongation inhibition. AUC comparisons dogs after simultaneous iv (3H) intraportal (14C) infusions indicate that only 8% reaching systemic circulation unchanged. Approximately 98% 96% was bound to human dog plasma protein, respectively. physiological disposition appears be suitable paradigm man. should both specific selective respect inhibition