Avas Mechanism of Action

Atorvastatin calcium is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA). The enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the synthesis of cholesterol.
Pharmacology: HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the major rate-limiting step in the cholesterol synthesis pathway. Avas is a selective, competitive inhibitor of HMG-CoA reductase, as a result, cholesterol synthesis is inhibited. The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to up regulation of LDL-receptors and an increase in LDL-catabolism. There is also some reduction of LDL production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol.
Avas reduces total cholesterol, LDL-C and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia and mixed dyslipidemias. Avas also reduces VLDL-C and TG and produces variable increase in HDL-C and apolipoprotein A1. Avas reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid lowering medications.
Pharmacokinetics: Avas is rapidly absorbed after oral administration; maximum plasma levels occur within 1 or 2 hrs. The absolute bioavailability of Avas (parent drug) is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity approximately 30%. Although food reduces the rate and extent of absorption by approximately 25% and 9%, respectively, as assessed by C_max and AUC, LDL-C reduction is similar whether Avas is given with or without food.
Plasma concentrations of Avas are lower (approximately 30% for C_max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. The mean volume of distribution of Avas is approximately 565 L. Avas is approximately 98% bound to plasma proteins.
Avas is extensively metabolized to ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Avas. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Avas and its metabolites are eliminated primarily in the bile following hepatic and/or extra hepatic metabolism; however, Avas does not appear to undergo enterohepatic circulation. The mean plasma elimination half-life of Avas in humans is approximately 14 hrs, but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hrs due to the contribution of active metabolites. In a dose of Avas, <2% is recovered in urine following oral administration.