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Atorvastatin
Lipitor™
LIPITOR TABLETS(TAB FILM C 20 mg ) [1 of 3]
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-------------------------------------------------------------------------------Description: Atorvastatin is a selective, competitive HMG-CoA reductase inhibitor. Atorvastatin is
primarily used to lower cholesterol and triglycerides in patients with hypercholesterolemia and
mixed dyslipidemia. At the maximum recommended dosage, atorvastatin has greater LDLlowering efficacy relative to the maximum recommended dosage of other HMG-CoA reductase
inhibitors. In a dose-dependent manner, atorvastatin lowers LDL cholesterol by as much as 60%;
doses as low as 2.5 mg/day were as effective as lower doses of other HMG-CoA reductase
inhibitors.[1378] Atorvastatin doses of 10—80 mg once daily result in mean LDL reductions
ranging from 43—60%. Triglycerides are lowered in patients with hypertriglyceridemia by as
much as 45%[1379] and HDL cholesterol increases by as much as 12% with atorvastatin
monotherapy. The combination of atorvastatin and colestipol produced a 10% greater reduction in
LDL-cholesterol than atorvastatin alone, however, adverse reactions were greater and
compliance was lower for the combination.[1380] Atorvastatin's unique structure, long half-life,
and hepatic selectivity may explain its greater LDL-lowering potency compared to other HMGCoA reductase inhibitors. Atorvastatin may also be used in the treatment of homozygous familial
hypercholesterolemia. Final FDA approval for atorvastatin was granted on December 18, 1996.
Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme
responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol.
Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces
cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and
increased hepatic uptake of LDL-cholesterol from the circulation. Atorvastatin ultimately reduces
the levels of circulating total cholesterol, LDL-cholesterol, and serum triglycerides. Drug dosage
rather than systemic drug concentration correlates better with LDL-cholesterol reduction. As with
other HMG-CoA reductase inhibitors, atorvastatin exhibits no effects on antipyrine hepatic
metabolism.[1381]
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum
concentrations; the clinical significance of these effects is unknown.
Pharmacokinetics: Atorvastatin is administered orally. Following oral administration, the drug is
rapidly absorbed with peak plasma concentrations occurring within 1—2 hours. The extent of
absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability is
approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is
approximately 30%. Presystemic clearance and/or hepatic first-pass metabolism accounts for the
low systemic bioavailability. Food decreases the rate and extent of atorvastatin absorption by
approximately 25% and 9%, respectively, however, LDL-cholesterol reduction is similar whether
the drug is given with or without food. Similarly, atorvastatin plasma concentrations are lower
following evening doses compared with morning dosing and LDL-cholesterol reduction is the
same regardless of the time of day the drug is administered. Atorvastatin plasma concentrations
are higher in healthy elderly patients than in young adults, however, LDL-cholesterol reduction is
comparable. Atorvastatin is >= 98% bound to plasma proteins. A blood/plasma ratio of 0.25
indicates poor drug penetration into red blood cells. Animal data reveal that atorvastatin is likely
to be secreted in human milk.
Atorvastatin undergoes extensive metabolism to active ortho- and parahydroxylated metabolites
which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity.
Based on in vitro studies, cytochrome P450 3A4 may also contribute to the metabolism of
atorvastatin. In animals, the ortho-hydroxy metabolite is further metabolized by glucuronidation.
Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or
extrahepatic metabolism. It does not appear that the drug undergoes enterohepatic recirculation.
Less than 2% of a dose is recovered in the urine following oral administration. The mean plasma
elimination half-life of atorvastatin in humans is approximately 14 hours, however, the half-life of
HMG-CoA reductase inhibitory activity is 20—30 hours because of the active metabolites.
Plasma concentrations of atorvastatin are higher (about 40% for Cmax and 30% for AUC) in
healthy elderly subjects than in young adults. In addition, the LDL-cholesterol reduction is also
greater that seen in younger patient populations given equivalent doses atorvastatin.
[ Revised 2/18/02 ]
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