Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Viatris Healthcare (Pty) Ltd, 4 Brewery Street, Isando, Gauteng, 1601
A 7.5 Serum-cholesterol reducers
Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors
ATC code: C10AA05
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.
Atorvastatin lowers plasma cholesterol and lipoprotein levels in animal models 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. It reduces LDL-C production and the number of LDL-C particles.
After oral administration maximum plasma concentrations occur within 1–2 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 gastro-intestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of medicine 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 medicine administration compared to morning administration. LDL-C reduction is the same regardless of the time of medicine administration (see section 4.2).
Mean volume of distribution of atorvastatin is approximately 381 litres. It is 98% or more bound to plasma proteins.
It is extensively metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro 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.
It 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 are higher 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 atorvastatin.
No pharmacokinetic data in the paediatric population is available.
Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin.
Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child–Pugh B).
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