Atorvastatin (INN) ( ) (Lipitor, Pfizer), is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms.

Atorvastatin inhibits HMG-CoA reductase, the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol.

Atorvastatin was first synthesized in 1985 by Bruce Roth while working at Parke-Davis Warner-Lambert Company (now Pfizer).

With 2006 sales of US$12.9 billion, Lipitor is the largest-selling drug in the world.

Lipitor is not the only statin; there are several other statins on the market.

Pharmacology

main: Statin

As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.

In clinical trials, adding ezetimibe (Zetia) to Lipitor lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin). Fact: date=August 2007

Pharmacokinetics

Atorvastatin has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1-2 hours. The absolute bioavailability of atorvastatin is approximately 14%, however, the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Food has shown to reduce the rate and extent of atorvastatin absorption. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of atorvastatin. Evening atorvastatin dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) by 30% each. However, time of administration does not affect the plasma LDL-C lowering efficacy of atorvastatin.

Atorvastatin is highly protein bound (≥98%) with a blood/plasma concentration ratio of 0.25 indicating a low red blood cell distribution.

The primary proposed mechanism of atorvastatin metabolism is through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme it has shown susceptibility to inhibitors and inducers of CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. Atorvastatin is also an inhibitor of cytochrome 3A4.