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Identification
NameCerivastatin
Accession NumberDB00439  (APRD00102)
TypeSmall Molecule
GroupsWithdrawn
Description

On August 8, 2001 the U.S. Food and Drug Administration (FDA) announced that Bayer Pharmaceutical Division voluntarily withdrew Baycol from the U.S. market, due to reports of fatal Rhabdomyolysis, a severe adverse reaction from this cholesterol-lowering (lipid-lowering) product. It has also been withdrawn from the Canadian market.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Cerivastatin sodium
143201-11-0
Thumb
  • InChI Key: GPUADMRJQVPIAS-QCVDVZFFSA-M
  • Monoisotopic Mass: 481.224046051
  • Average Mass: 481.5321
DBSALT000330
Brand names
NameCompany
BaycolNot Available
LipobayNot Available
RivastatinNot Available
Brand mixturesNot Available
Categories
CAS number145599-86-6
WeightAverage: 459.5503
Monoisotopic: 459.242101408
Chemical FormulaC26H34FNO5
InChI KeySEERZIQQUAZTOL-ANMDKAQQSA-N
InChI
InChI=1S/C26H34FNO5/c1-15(2)25-21(11-10-19(29)12-20(30)13-23(31)32)24(17-6-8-18(27)9-7-17)22(14-33-5)26(28-25)16(3)4/h6-11,15-16,19-20,29-30H,12-14H2,1-5H3,(H,31,32)/b11-10+/t19-,20-/m1/s1
IUPAC Name
(3R,5S,6E)-7-[4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid
SMILES
COCC1=C(C2=CC=C(F)C=C2)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C(C(C)C)N=C1C(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyridines and Derivatives
SubclassPhenylpyridines
Direct parentPhenylpyridines
Alternative parentsFluorobenzenes; Beta Hydroxy Acids and Derivatives; Heterocyclic Fatty Acids; Unsaturated Fatty Acids; Aryl Fluorides; Secondary Alcohols; Dialkyl Ethers; Enolates; Polyamines; Carboxylic Acids; Organofluorides
Substituentsbeta-hydroxy acid; fluorobenzene; hydroxy acid; aryl halide; benzene; aryl fluoride; secondary alcohol; polyamine; carboxylic acid derivative; enolate; ether; carboxylic acid; dialkyl ether; organofluoride; alcohol; organonitrogen compound; organohalogen
Classification descriptionThis compound belongs to the phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.
Pharmacology
IndicationUsed as an adjunct to diet for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb) when the response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures alone has been inadequate.
PharmacodynamicsCerivastatin, a competitive HMG-CoA reductase inhibitor effective in lowering LDL cholesterol and triglycerides, is used to treat primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb).
Mechanism of actionCerivastatin competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the hepatic enzyme responsible for converting HMG-CoA to mevalonate. As mevalonate is a precursor of sterols such as cholesterol, this results in a decrease in cholesterol in hepatic cells, upregulation of LDL-receptors, and an increase in hepatic uptake of LDL-cholesterol from the circulation.
AbsorptionThe mean absolute oral bioavailability 60% (range 39 - 101%).
Volume of distributionNot Available
Protein bindingMore than 99% of the circulating drug is bound to plasma proteins (80% to albumin).
Metabolism

Hepatic. Biotransformation pathways for cerivastatin in humans include the following: demethylation of the benzylic methyl ether to form Ml and hydroxylation of the methyl group in the 6'-isopropyl moiety to form M23.

SubstrateEnzymesProduct
Cerivastatin
HydroxycerivastatinDetails
Cerivastatin
DesmethylcerivastatinDetails
Route of eliminationNot Available
Half life2-3 hours
ClearanceNot Available
ToxicityRhabdomyolysis, liver concerns
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9628
Blood Brain Barrier + 0.9381
Caco-2 permeable + 0.5141
P-glycoprotein substrate Substrate 0.6231
P-glycoprotein inhibitor I Non-inhibitor 0.5221
P-glycoprotein inhibitor II Non-inhibitor 0.719
Renal organic cation transporter Non-inhibitor 0.8848
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.672
CYP450 1A2 substrate Non-inhibitor 0.67
CYP450 2C9 substrate Non-inhibitor 0.64
CYP450 2D6 substrate Non-inhibitor 0.8717
CYP450 2C19 substrate Non-inhibitor 0.596
CYP450 3A4 substrate Non-inhibitor 0.6191
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5668
Ames test Non AMES toxic 0.817
Carcinogenicity Non-carcinogens 0.8706
Biodegradation Not ready biodegradable 0.9881
Rat acute toxicity 2.6748 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9901
hERG inhibition (predictor II) Non-inhibitor 0.8623
Pharmacoeconomics
Manufacturers
  • Bayer pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States51770801994-11-262011-11-26
Canada13407981999-10-262016-10-26
Canada20574441998-05-262011-12-11
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityHighly solubilityNot Available
logP3.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00419ALOGPS
logP4.15ALOGPS
logP2.67ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)4.05ChemAxon
pKa (Strongest Basic)5.58ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area99.88 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity126.82 m3·mol-1ChemAxon
Polarizability50.23 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Furberg CD, Pitt B: Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2(5):205-207. Pubmed
External Links
ResourceLink
KEGG CompoundC07966
PubChem Compound446156
PubChem Substance46505877
ChemSpider393588
BindingDB18376
ChEBI3558
ChEMBL
Therapeutic Targets DatabaseDNC000403
PharmGKBPA448897
HET116
Drug Product Database2237325
RxListhttp://www.rxlist.com/cgi/generic/cerivastat.htm
Drugs.comhttp://www.drugs.com/mtm/cerivastatin.html
WikipediaCerivastatin
ATC CodesC10AA06
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(144 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
BezafibrateIncreased risk of myopathy/rhabdomyolysis
BosentanBosentan may decrease the serum concentration of cerivastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if bosentan is initiated, discontinued or dose changed.
ClarithromycinThe macrolide, clarithromycin, may increase the toxicity of the statin, cerivastatin.
ColchicineIncreased risk of rhabdomyolysis with this combination
CyclosporinePossible myopathy and rhabdomyolysis
DiltiazemDiltiazem may increase the serum concentration of cerivastatin. Cerivastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.
ErythromycinThe macrolide, erythromycin, may increase the toxicity of the statin, cerivastatin.
FenofibrateIncreased risk of myopathy/rhabdomyolysis
GemfibrozilIncreased risk of myopathy/rhabdomyolysis
ImatinibImatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of cerivastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if imatinib is initiated, discontinued or dose changed.
ItraconazoleIncreased risk of myopathy/rhabdomyolysis
JosamycinThe macrolide, josamycin, may increase the toxicity of the statin, cerivastatin.
KetoconazoleIncreased risk of myopathy/rhabdomyolysis
NefazodoneNefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of cerivastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if nefazodone is initiated, discontinued or dose changed.
QuinupristinThis combination presents an increased risk of toxicity
RifabutinRifabutin may decrease the effect of cerivastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of cerivastatin if rifabutin is initiated, discontinued or dose changed.
RifampicinRifampin may decrease the effect of cerivastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of cerivastatin if rifampin is initiated, discontinued or dose changed.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment as grapefruit can significantly increase serum levels of this product.
  • Take without regard to meals.

Targets

1. 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
3-hydroxy-3-methylglutaryl-coenzyme A reductase P04035 Details

References:

  1. Shiomi M, Ito T: Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol. 1999 Feb;126(4):961-8. Pubmed
  2. Blumenthal RS: Statins: effective antiatherosclerotic therapy. Am Heart J. 2000 Apr;139(4):577-83. Pubmed
  3. Ganne F, Vasse M, Beaudeux JL, Peynet J, Francois A, Mishal Z, Chartier A, Tobelem G, Vannier JP, Soria J, Soria C: Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes—a possible protective mechanism against atherothrombosis. Thromb Haemost. 2000 Oct;84(4):680-8. Pubmed
  4. Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ: Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin. Clin Cancer Res. 2001 Jul;7(7):2067-75. Pubmed
  5. Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP, Soria J, Soria C: Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis. 2001 Aug;22(8):1139-48. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Neuvonen PJ, Niemi M, Backman JT: Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006 Dec;80(6):565-81. Pubmed
  2. Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH: Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos. 2000 Dec;21(9):353-64. Pubmed
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  4. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  5. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  6. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M: Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved. Drug Metab Dispos. 1997 Mar;25(3):321-31. Pubmed
  7. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ: Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002 Dec;30(12):1352-6. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Neuvonen PJ, Niemi M, Backman JT: Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006 Dec;80(6):565-81. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  5. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ: Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002 Dec;30(12):1352-6. Pubmed

5. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH: Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos. 2000 Dec;21(9):353-64. Pubmed

6. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH: Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos. 2000 Dec;21(9):353-64. Pubmed

7. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH: Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos. 2000 Dec;21(9):353-64. Pubmed
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

8. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. Pubmed

2. Canalicular multispecific organic anion transporter 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

References:

  1. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. Pubmed

3. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. Pubmed

4. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, Sugiyama Y: Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67. Epub 2005 May 18. Pubmed
  2. Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K: Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics. 2005 Jul;15(7):513-22. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10