the comprehensive pharmacology reference atorvastatin
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Atorvastatin
Monica Valentovic Marshall University, Huntington, USA
2007 Elsevier Inc. All rights reserved.
Introduction
Atorvastatin is used for the treatment of hypercholesterolemia and hypertriglyceridemia.
Atorvastatin, and the newer rosuvastatin, are the only members of this class of agents
(statins) currently approved for both uses. The mechanism of action for atorvastatin is
competitive, reversible inhibition of HMG CoA reductase (EC 1.1.1.34), the rate-limiting
enzyme in cholesterol synthesis. Atorvastatin is taken orally at 10, 20, 40, and 80 mg/day
for the treatment of hypercholesterolemia. As for other statins, major adverse effect
associated with the use of atorvastatin is an increased risk of rhabdomyolysis. Atorvastatin
can decrease total cholesterol by 50%.
NomenclatureName of the Clinical
Form
Atorvastatin calcium
Related Names
Source:EMTREE
Atorvastatin; (R,R)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-
(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H-
pyrrole-1-heptanoicacid; (R-(R*,R*))-2-(4-Fluorophenyl)-
beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-
((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid;
atorvastatin calcium; ci 981; 2 (4 fluorophenyl) beta,delta
dihydroxy 5isopropyl 3 phenyl 4 phenylcarbamoyl 1h pyrrole
1 heptanoic acid; lipibec; lipitor; sortis; torvast; ym 548;
zarator; (R,R)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-
methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H-
pyrrole-1-heptanoic acid; 2 (4 fluorophenyl) beta,delta
dihydroxy 5 isopropyl 3 phenyl 4 phenylcarbamoyl 1h pyrrole
1 heptanoic acid; ci981; ym548
Chemical Names Calcium (betaR,deltaR)-2-(p-fluorophenyl)-beta,delta-
dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)
pyrrole-1-heptanoic
CAS Number 134523-00-5
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Basic ChemistryChemical Structure
Structure
Comments atorvastatin: C33 H34F N2O5; atorvastatin calcium: (C33 H34 F N2O5 )
2Ca.3H2O
Chemical
Formula
C33 H35 F N2 O5
Properties
Physical
Properties
Atorvastatin is an off-white crystalline powder.
Molecular
Weight
558.646
Solubility Atorvastatin calcium is slightly soluble in water or phosphate buffer at
pH 7.4, and freely soluble in methanol (http://www.rxlist.com/cgi/
generic/atorvastatin.htm).
Human Pharmacokinetics
Following oral administration, atorvastatin undergoes extensive first-pass metabolism by
CYP3A4 in the intestinal wall and liver. While it has a half-life of 14 hours, it is effective
for 2030 hours. No dosage adjustment is necessary for those with diminished renal
function because atorvastatin is not extensively excreted in urine. Atorvastatin is a
substrate of the hepatic organic anion transport protein (OATP)Lennernas (2003).
Pharmacokinetic Properties
Value Units
Prep. and
Route of Admin. Reference Comments
Absorption Atorvastatin is well-absorbed following oral administration but undergoes
extensive first-pass metabolismWilliams and Feely (2002). The Cmax
occurs within 12 hours. Food slows the rate of absorption and decreases
by 9% the extent of absorption.
Bioavailability 14 % p.o. Drug Facts and
Comparisons
(2001)
The low
bioavailability of
atorvastatin is due
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to extensive first-
pass metabolism.
Distribution
Volume of Distribution 381 L Physicians Desk
Reference (2004)
Plasma Protein Binding >98 % Drug Facts and
Comparisons
(2001)
Metabolism Atorvastatin is a substrate for CYP 3A4. Hydroxyl metabolites, ortho- and
para-hydroxyl metabolites are pharmacologically active. The metabolites
comparable to the parent compound in vitro as inhibitors of HMG CoA
reductase.
Plasma Half-Life 14 hrs Drug Facts and
Comparisons
(2001)
The half-life of the
active metabolite
is 2030 hours.
Bio Half-Life
Clearance 625 ml/
min
Lennernas (2003)
Routes of Elimination Less than 2% of an administered dose of atorvastatin is excreted in urine.
The majority of the drug and its metabolites are excreted in bile.
Targets-Pharmacodynamics
Atorvastatin is a competitive, reversible inhibitor of HMG CoA reductase (EC 1.1.1.34),
the rate limiting enzyme in cholesterol synthesis. Inhibition of HMG CoA reductase
increases formation of surface hepatic LDL receptors that enhances LDL clearance from
the circulation.
Target Name(s):
HMG CoA reductase
Therapeutics
Atorvastatin is used for the treatments of hypercholesterolemia and hypertriglyceridemia.
Atorvastatin is approved for use in individuals with IIa, IIb, III, and IV hyperlipidemias.
Plasma cholesterol levels are reduced within 24 hours and LDL-cholesterol is reduced
within 3 days. Peak effects occur within 2 weeks Stern et al (2000).
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Indications
Value Units
Prep. and
Route of
Admin. Reference Comments
HypercholesterolemiaDosage 1080 mg/day tablets, p.o. Drug Facts and
Comparisons
(2001)
The initial dosage should be 10 mg/day.
Atorvastatin can be taken at any time of
day. This differs from all other statins
which must be taken in the evening for
greatest effectiveness. ALT and CPK
blood levels should be monitored every 4
weeks for the first 3 months of therapy,
and then every 6 months after stabilization
of dosageA to Z Drug Facts (1999).
Hypertriglyceridemia
Dosage 1080 mg/day tablets, p.o. Drug Facts and
Comparisons
(2001)
The initial dosage should be 10 mg/day.
Atorvastatin can be taken at any time of
day. This differs from all other statins
which must be taken in the evening forgreatest effectiveness. ALT and CPK
blood levels should be monitored every 4
weeks for the first 3 months of therapy,
and then every 6 months after stabilization
of dosageA to Z Drug Facts (1999).
Mixed Dysbetalipoproteinemia III
Dosage 1080 mg/day tablets, p.o. Drug Facts and
Comparisons
(2001)
The initial dosage should be 10 mg/day.
Atorvastatin can be taken at any time of
day. This differs from all other statins
which must be taken in the evening for
greatest effectiveness. ALT and CPK
blood levels should be monitored every 4
weeks for the first 3 months of therapy,and then every 6 months after stabilization
of dosageA to Z Drug Facts (1999).
Mixed Dyslipidemia IIa and IIb
Dosage 1080 mg/day tablets, p.o. Drug Facts and
Comparisons
(2001)
The initial dosage should be 10 mg/day.
Atorvastatin can be taken at any time of
day. This differs from all other statins
which must be taken in the evening for
greatest effectiveness. ALT and CPK
blood levels should be monitored every 4
weeks for the first 3 months of therapy,
and then every 6 months after stabilization
of dosageA to Z Drug Facts (1999).
Contraindications
Atorvastatin is contraindicated in pregnancy (Category X), during lactation, and in those
with elevated plasma liver enzymes or active liver diseaseA to Z Drug Facts (1999).
Adverse Effects
Adverse effects associated with the use of atorvastatin include headache, diarrhea, and
myalgia sinusitis. Administration should be discontinued if CPK or ALT levels increased
3-fold.
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Agent-Agent Interactions
Agent Name Mode of Interaction
Erythromycin By inhibiting CYP450, erythromycin increases blood levels of
atorvastatin.
Oral contraceptives Atorvastatin increases the plasma levels of estrogen and
progesterone.
Antacids Antacids decrease the oral bioavailability of atorvastatin.
Nicotinic acid Thereis anIncreased risk ofmyopathy whentakenconcurrently with
atorvastatinKlotz (2003).
Gemfibrozil Thereis anIncreased risk ofmyopathy whentakenconcurrently with
atorvastatinKlotz (2003).
Azole Antifungals There is an Increased risk of myopathy when taken concurrently with
atorvastatinKlotz (2003).
Grapefruit juice There is an Increased risk ofmyopathy whentaken concurrently with
atorvastatinKlotz (2003).
Pre-Clinical Research
Other Research
Statins have effects that cannot be attributed to inhibition of hepatic cholesterol synthesis.For example, atorvastatin induces apoptotic changes in rat pulmonary vein endothelial
cells Kaneta et al (2003). Moreover, endothelial cells exposed to atorvastatin display
increased DNA laddering, decreased cell viability, and increased activity of caspase-3.
Statins decrease nitrotyrosine adducted proteins suggesting they may reduce oxidative
damage mediated by reactive nitrogen radicals. In humans, atorvastatin decreases
the levels of chlorotyrosine and dityrosine, suggesting diminished oxidative damageShishehbor et al (2003).
Other Information Web Sites
http://www.rxlist.com/cgi/generic/atorvastatin.htm
Journal Citations
Kaneta, S., Satoh, K., Kano, S., Kanda, M., Ichihara, K., 2003. All hydrophobic HMG-CoA reductase
inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis, 170(2),
237243.
Lennernas, H., 2003. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet., 42(13), 11411160.
Shishehbor, M.H., Brennan, M.L., Aviles, R.J., Fu, X., Penn, M.S., Sprecher, D.L., Hazen, S.L., 2003. Statins
promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation, 108(4),
426431.
Stern, R.H., Yang, B.B., Hounslow, N.J., MacMahon, M., Abel, R.B., Olson, S.C., 2000. Pharmacodynamics
and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an HMG-CoA reductase inhibitor.
J. Clin. Pharmacol., 40, 616623.
Klotz, U., 2003. Pharmacological comparison of the statins. Arzneimittelforschung, 53(9), 605611.
Williams, D., Feely, J., 2002. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA
reductase inhibitors.Clin. Pharmacokinet., 41(5), 343370.
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Book Citations
Drug Facts and Comparisons 2001 HMG CoA Reductase Inhibitors. Cada, D.J. (Ed.), Drug Facts and
Comparisons, Edition 5, pp. 289293, Facts and Comparisons, St. Louis, Mo.
A to Z Drug Facts 1999 Tatro, D.S. (Ed.), A to Z Drug Facts. Facts and Comparisons, St. Louis, Mo.
Physicians Desk Reference 2004 Atorvastatin. Duplay, D. (Ed.), Physicians Desk Reference, Edition 58,
pp. 26062610, Thomson, Montvale, NJ.
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