Source: Web Search Publisher: Pharmacia South Africa (Pty) Limited, 85 Bute Lane, Sandton, 2196, South Africa
Pharmacological classification: A 7.5 Serum-cholesterol reducer
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
The liver is its primary site of action and the principal site of cholesterol synthesis and low-density lipoprotein cholesterol (LDL-C) clearance.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of LDL-C receptors on the cell-surface of liver cells, providing for enhanced uptake and catabolism of LDL-C. Atorvastatin reduces LDL-C production and the number of LDL-C particles. Depending on dose, atorvastatin reduces the number of apolipoprotein-B-containing particles in patients with hypercholesterolaemia. Atorvastatin produces a profound and sustained increase in LDL-C receptor activity coupled with a change in the quality of circulating LDL-C particles.
Atorvastatin reduces total cholesterol (total-C), LDL-C, apolipoprotein-B in normal volunteers, and in patients with heterozygous familial hypercholesterolaemia, non-familial hypercholesterolaemia, mixed dyslipidaemia, and in some patients with homozygous familial hypercholesterolaemia. It also reduces serum triglycerides (TG) and produces variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A-1 in non-familial hypercholesterolaemia and mixed dyslipidaemias.
Following oral administration; maximum plasma concentrations occur within 1 to 2 hours. The absolute bioavailability of atorvastatin (parent substance) is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared to morning administration. However, LDL-C reduction is the same regardless of the time of drug administration (see DOSAGE AND DIRECTIONS FOR USE).
Mean volume of distribution of atorvastatin is approximately 381litres. Atorvastatin is 98% or more bound to plasma proteins.
Atorvastatin is extensively metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Invitro inhibition of HMG-CoA reductase by ortho-and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, it does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin (parent substance) in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (65 years and older) than in young adults. LDL-C reduction is comparable to that seen in younger patient populations given equal doses of ASPAVOR.
Pharmacokinetic data in the paediatric population are not available.
Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men; however, there is no clinically significant difference in LDL-C reduction with ASPAVOR between men and women.
Plasma concentrations of atorvastatin are similar in black and white subjects.
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