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)




which must be taken in the evening forgreatest effectiveness. ALT and CPK





Mixed Dysbetalipoproteinemia III


Comparisons

(2001)







weeks for the first 3 months of therapy,and then every 6 months after stabilization


Mixed Dyslipidemia IIa and IIb


Comparisons

(2001)










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


Azole Antifungals There is an Increased risk of myopathy when taken concurrently with


Grapefruit juice There is an Increased risk ofmyopathy whentaken concurrently with


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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the comprehensive pharmacology reference atorvastatin

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