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Atorvastatin (T3D4980)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (3)XML
Targets (3)
Record Information
Version2.0
Creation Date2014-10-14 21:18:31 UTC
Update Date2014-12-24 20:27:01 UTC
Accession NumberT3D4980
Identification
Common NameAtorvastatin
ClassSmall Molecule
DescriptionAtorvastatin (Lipitor) is a member of the drug class known as statins. It is used for lowering cholesterol. Atorvastatin is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in cholesterol biosynthesis via the mevalonate pathway. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate. Atorvastatin acts primarily in the liver. Decreased hepatic cholesterol levels increases hepatic uptake of cholesterol and reduces plasma cholesterol levels.
Compound Type
  • Anticholesteremic Agent
  • Drug
  • Hydroxymethylglutaryl-CoA Reductase Inhibitor
  • Metabolite
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
Atogal
Atorvastatin acid
Atorvastatin calcium
Cardyl
Faboxim
Hipolixan
Lipitor
Lipotropic
Lipovastatinklonal
Liprimar
Lowden
Normalip
Sincol
Sortis
Torvacard
Torvast
Totalip
Tulip
Vastina
Xanator
Xarator
Zurinel
Chemical FormulaC33H34FN2O5
Average Molecular Mass557.632 g/mol
Monoisotopic Mass557.246 g/mol
CAS Registry Number134523-00-5
IUPAC Name7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate
Traditional Name7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoate
SMILESCC(C)C1=C(C(O)=NC2=CC=CC=C2)C(=C(N1CCC(O)CC(O)CC([O-])=O)C1=CC=C(F)C=C1)C1=CC=CC=C1
InChI IdentifierInChI=1/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/p-1
InChI KeyInChIKey=XUKUURHRXDUEBC-UHFFFAOYNA-M
Chemical Taxonomy
Description belongs to the class of organic compounds known as aminophenyl ethers. These are aromatic compounds that contain a phenol ether, which carries an amine group on the benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenol ethers
Sub ClassAminophenyl ethers
Direct ParentAminophenyl ethers
Alternative Parents
Substituents
  • Aminophenyl ether
  • Methoxyaniline
  • Phenoxy compound
  • Anisole
  • Aniline or substituted anilines
  • Methoxybenzene
  • Alkyl aryl ether
  • Monocyclic benzene moiety
  • Ether
  • Organopnictogen compound
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Organic oxygen compound
  • Amine
  • Hydrocarbon derivative
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Liver
  • Platelet
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceNot Available
Experimental Properties
PropertyValue
Melting Point159.2-160.7 °C
Boiling PointNot Available
SolubilitySodium salt soluble in water, 20.4 ug/mL (pH 2.1), 1.23 mg/mL (pH 6.0)
LogP5.7
Predicted Properties
PropertyValueSource
Water Solubility0.0005 g/LALOGPS
logP4.41ALOGPS
logP5.39ChemAxon
logS-6.1ALOGPS
pKa (Strongest Acidic)4.33ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area114.62 ŲChemAxon
Rotatable Bond Count12ChemAxon
Refractivity169.04 m³·mol⁻¹ChemAxon
Polarizability59.7 ųChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0aor-0000090000-401e9c7a2f170820f7292016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014j-0000090000-647b0fa490907c33201c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000j-4200790000-a372fe1f0093d1e98cd32016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-2100090000-fe1fdeff5a26f7f838822016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-8400090000-7dd2f7f373fb6fd5de882016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-9500120000-34427c424cc44ee990742016-08-03View Spectrum
Toxicity Profile
Route of ExposureAtorvastatin is rapidly absorbed after oral administration with maximum plasma concentrations achieved in 1 to 2 hours. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance by gastrointestinal mucosa and first-pass metabolism in the liver.
Mechanism of ToxicityAtorvastatin selectively and competitively inhibits the hepatic enzyme HMG-CoA reductase. As HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway, this results in a subsequent decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations.
MetabolismAtorvastatin is extensively metabolized 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. CYP3A4 is also involved in the metabolism of atorvastatin.
Toxicity ValuesGenerally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesMay be used as primary prevention in individuals with multiple risk factors for coronary heart disease (CHD) and as secondary prevention in individuals with CHD to reduce the risk of myocardial infarction (MI), stroke, angina, and revascularization procedures. May be used to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS). May be used in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia, and/or hypertriglyeridemia as an adjunct to dietary therapy to decrease serum total and low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and triglyceride concentrations, while increasing high-density lipoprotein cholesterol (HDL-C) levels.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01076
HMDB IDHMDB05006
PubChem Compound ID60823
ChEMBL IDCHEMBL1487
ChemSpider ID54810
KEGG IDC06834
UniProt IDNot Available
OMIM ID
ChEBI ID2910
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB ID117
ACToR IDNot Available
Wikipedia LinkAtorvastatin
References
Synthesis Reference

Zlatko Pflaum, “Process for the preparation of amorphous atorvastatin.” U.S. Patent US20020183527, issued December 05, 2002.

MSDST3D4980.pdf
General References
  1. Rouleau J: Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Am J Med. 2005 Dec;118 Suppl 12A:28-35. [16356805 ]
  2. Maggon K: Best-selling human medicines 2002-2004. Drug Discov Today. 2005 Jun 1;10(11):739-42. [15922927 ]
  3. Taylor PJ, Kubler PA, Lynch SV, Allen J, Butler M, Pillans PI: Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. Ann Pharmacother. 2004 Feb;38(2):205-8. Epub 2003 Dec 19. [14742751 ]
  4. Funatsu T, Suzuki K, Goto M, Arai Y, Kakuta H, Tanaka H, Yasuda S, Ida M, Nishijima S, Miyata K: Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells. Atherosclerosis. 2001 Jul;157(1):107-15. [11427209 ]
  5. Tannous M, Cheung R, Vignini A, Mutus B: Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic subjects. Thromb Haemost. 1999 Nov;82(5):1390-4. [10595624 ]
  6. Naoumova RP, Dunn S, Rallidis L, Abu-Muhana O, Neuwirth C, Rendell NB, Taylor GW, Thompson GR: Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin. J Lipid Res. 1997 Jul;38(7):1496-500. [9254075 ]
  7. Izar MC: [Hypolipidemic treatment under special conditions: posttransplant and/or immunosuppressive therapy]. Arq Bras Cardiol. 2005 Oct;85 Suppl 5:50-7. Epub 2006 Jan 2. [16400400 ]
  8. Hwang YS, Tsai WC, Lu YH, Lin CC, Chen YF: Effect of atorvastatin on the expression of CD40 ligand and P-selectin on platelets in patients with hypercholesterolemia. Am J Cardiol. 2004 Aug 1;94(3):364-6. [15276107 ]
  9. Bruni F, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palazzuoli A, Sawamura T, Gioffre WR, Auteri A, Puccetti L: Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects. Clin Appl Thromb Hemost. 2005 Oct;11(4):417-28. [16244767 ]
  10. Fenton JW 2nd, Brezniak DV, Ofosu FA, Shen GX, Jacobson JR, Garcia JG: Statins and thrombin. Curr Drug Targets Cardiovasc Haematol Disord. 2005 Apr;5(2):115-20. [15853752 ]
  11. Pokrovskaia EV, Vaulin NA, Gratsianskii NA, Averkov OV, Deev AD: [Markers of inflammation and platelet aggregation in patients with non ST elevation acute coronary syndrome treated with atorvastatin or pravastatin]. Kardiologiia. 2003;43(1):7-18. [12891281 ]
  12. Funatsu T, Kakuta H, Tanaka H, Arai Y, Suzuki K, Miyata K: [Atorvastatin (Lipitor): a review of its pharmacological and clinical profile]. Nihon Yakurigaku Zasshi. 2001 Jan;117(1):65-76. [11233299 ]
  13. Tousoulis D, Bosinakou E, Kotsopoulou M, Antoniades C, Katsi V, Stefanadis C: Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina. Int J Cardiol. 2006 Jan 26;106(3):333-7. [16337041 ]
  14. Malinowski JM: Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. Am J Health Syst Pharm. 1998 Nov 1;55(21):2253-67; quiz 2302-3. [9825877 ]
  15. DailyMed FDA Label [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. 3-hydroxy-3-methylglutaryl-coenzyme A reductase
General Function:
Nadph binding
Specific Function:
Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
Gene Name:
HMGCR
Uniprot ID:
P04035
Molecular Weight:
97475.155 Da
References
  1. Davidson MH: Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs. 2002 Mar;11(3):125-41. [12769127 ]
  2. Jafari M, Ebrahimi R, Ahmadi-Kashani M, Balian H, Bashir M: Efficacy of alternate-day dosing versus daily dosing of atorvastatin. J Cardiovasc Pharmacol Ther. 2003 Jun;8(2):123-6. [12808485 ]
  3. Baxter JD, Webb P, Grover G, Scanlan TS: Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight. Trends Endocrinol Metab. 2004 May-Jun;15(4):154-7. [15109613 ]
  4. Maejima T, Yamazaki H, Aoki T, Tamaki T, Sato F, Kitahara M, Saito Y: Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell. Biochem Biophys Res Commun. 2004 Nov 12;324(2):835-9. [15474503 ]
  5. Bosel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, Megow D, Dirnagl U, Hortnagl H, Fink KB, Endres M: Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem. 2005 Mar;92(6):1386-98. [15748157 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Target Details
2. Dipeptidyl peptidase 4
General Function:
Virus receptor activity
Specific Function:
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
Gene Name:
DPP4
Uniprot ID:
P27487
Molecular Weight:
88277.935 Da
References
  1. Taldone T, Zito SW, Talele TT: Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin. Bioorg Med Chem Lett. 2008 Jan 15;18(2):479-84. Epub 2007 Dec 3. [18068977 ]
Target Details
3. Aryl hydrocarbon receptor
General Function:
Transcription regulatory region dna binding
Specific Function:
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
Gene Name:
AHR
Uniprot ID:
P35869
Molecular Weight:
96146.705 Da
References
  1. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR: Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007 Jun;71(6):1475-86. Epub 2007 Feb 27. [17327465 ]
  2. Chauvin B, Drouot S, Barrail-Tran A, Taburet AM: Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. Clin Pharmacokinet. 2013 Oct;52(10):815-31. doi: 10.1007/s40262-013-0075-4. [23703578 ]