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Identification
NameCilostazol
Accession NumberDB01166  (APRD00155)
Typesmall molecule
Groupsapproved
Description

Cilostazol is a medication used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. It is manufactured by Otsuka Pharmaceutical Co. under the trade name Pletal. Although drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure, studies of significant size have not addressed people without the disease. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
CilostazoleNot AvailableNot Available
CilostazolumLatinINN
SaltsNot Available
Brand names
NameCompany
PletaalNot Available
PletalNot Available
Brand mixturesNot Available
Categories
CAS number73963-72-1
WeightAverage: 369.4607
Monoisotopic: 369.216475133
Chemical FormulaC20H27N5O2
InChI KeyRRGUKTPIGVIEKM-UHFFFAOYSA-N
InChI
InChI=1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
IUPAC Name
6-[4-(1-cyclohexyl-1H-1,2,3,4-tetrazol-5-yl)butoxy]-1,2,3,4-tetrahydroquinolin-2-one
SMILES
O=C1CCC2=C(N1)C=CC(OCCCCC1=NN=NN1C1CCCCC1)=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassQuinolines and Derivatives
SubclassQuinolones and Derivatives
Direct parentHydroquinolones
Alternative parentsHydroquinolines; Cyclitols and Derivatives; Phenol Ethers; Alkyl Aryl Ethers; Tetrazoles; Secondary Carboxylic Acid Amides; Carboxylic Acids; Polyamines
Substituentsphenol ether; cyclitol derivative; alkyl aryl ether; benzene; azole; cyclic alcohol; tetrazole; secondary carboxylic acid amide; carboxamide group; polyamine; ether; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the hydroquinolones. These are compounds containing an hydrogenated quinoline bearing a ketone group.
Pharmacology
IndicationFor the reduction of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest).
PharmacodynamicsCilostazol is a quinolinone derivative indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs.
Mechanism of actionCilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.
AbsorptionCilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known.
Volume of distributionNot Available
Protein binding95-98%
Metabolism

Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol.

Route of eliminationCilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol.
Half life11-13 hours.
ClearanceNot Available
ToxicityInformation on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Cilostazol Action PathwayDrug actionSMP00263
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9909
Caco-2 permeable - 0.5666
P-glycoprotein substrate Non-substrate 0.5361
P-glycoprotein inhibitor I Inhibitor 0.7886
P-glycoprotein inhibitor II Inhibitor 0.8387
Renal organic cation transporter Non-inhibitor 0.5794
CYP450 2C9 substrate Non-substrate 0.7887
CYP450 2D6 substrate Non-substrate 0.7734
CYP450 3A4 substrate Substrate 0.7407
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Inhibitor 0.7959
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9486
Ames test Non AMES toxic 0.5436
Carcinogenicity Non-carcinogens 0.9085
Biodegradation Not ready biodegradable 0.9636
Rat acute toxicity 1.9002 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7518
hERG inhibition (predictor II) Non-inhibitor 0.7075
Pharmacoeconomics
Manufacturers
  • Actavis totowa llc
  • Alphapharm party ltd
  • Apotex inc etobicoke site
  • Breckenridge pharmaceutical inc
  • Corepharma llc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Pliva hrvatska doo
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Otsuka pharmaceutical co ltd
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Pletal 100 mg tablet2.51USDtablet
Pletal 50 mg tablet2.39USDtablet
Cilostazol 100 mg tablet1.86USDtablet
Cilostazol 50 mg tablet1.86USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point160 °CPhysProp
logP2.3Not Available
Predicted Properties
PropertyValueSource
water solubility3.24e-02 g/lALOGPS
logP3.38ALOGPS
logP3.31ChemAxon
logS-4.1ALOGPS
pKa (strongest acidic)14.42ChemAxon
pKa (strongest basic)-0.51ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count1ChemAxon
polar surface area81.93ChemAxon
rotatable bond count7ChemAxon
refractivity117.13ChemAxon
polarizability41.15ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Marioara Mendelovici, “Processes for preparing cilostazol.” U.S. Patent US20020099213, issued July 25, 2002.

US20020099213
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01896
PubChem Compound2754
PubChem Substance46506317
ChemSpider2652
BindingDB50070490
ChEBI31401
ChEMBLCHEMBL799
Therapeutic Targets DatabaseDAP000191
PharmGKBPA164746334
RxListhttp://www.rxlist.com/cgi/generic/cilostaz.htm
Drugs.comhttp://www.drugs.com/cdi/cilostazol.html
WikipediaCilostazol
ATC CodesB01AC23
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(35.9 KB)
Interactions
Drug Interactions
Drug
DiltiazemDiltiazem, a moderate CYP3A4 inhibitor, may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cilostazol if diltiazem is initiated, discontinued or dose changed.
ErythromycinErythromycin increases the effect of cilostazol
FluconazoleFluconazole may decrease the effect of cilostazol.
FluoxetineFluoxetine, a moderate CYP2C19 inhibitor, may decrease the metabolism of cilostazol. Monitor for changes in the therapeutic and adverse effects of cilostazol if fluoxetine is initiated, discontinued or dose changed.
FluvoxamineFluvoxamine increases the effect of cilostazol
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
ItraconazoleItraconazole may increase the effect of cilostazol.
JosamycinErythromycin increases the effect of cilostazol
KetoconazoleKetoconazole may increase the effect of cilostazol.
NefazodoneNefazodone increases the effect of cilostazol
OmeprazoleOmeprazole increases the effect of cilostazol
SertralineSertraline increases the effect of cilostazol
TelithromycinTelithromycin may reduce clearance of Cilostazol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Cilostazol if Telithromycin is initiated, discontinued or dose changed.
TiclopidineTiclopidine may decrease the metabolism and clearance of Cilostazol. Consider alternate therapy or monitor for adverse/toxic effects of Cilostazol if Ticlopidine is initiated, discontinued or dose changed.
TreprostinilThe prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Cilostazol. Monitor for increased bleeding during concomitant thearpy.
VoriconazoleVoriconzole may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for increased therapeutic/adverse effects of cilostazol and consider reducing the dose during concomitant therapy.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment, grapefruit can significantly increase serum levels of this product.
  • Take on an empty stomach, a lipid rich meal will increase absorption.

Targets

1. cGMP-inhibited 3',5'-cyclic phosphodiesterase A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
cGMP-inhibited 3',5'-cyclic phosphodiesterase A Q14432 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Hong KW, Lee JH, Kima KY, Park SY, Lee WS: Cilostazol: therapeutic potential against focal cerebral ischemic damage. Curr Pharm Des. 2006;12(5):565-73. Pubmed
  3. Schror K: The pharmacology of cilostazol. Diabetes Obes Metab. 2002 Mar;4 Suppl 2:S14-9. Pubmed
  4. Mokry J, Mokra D, Nosalova G, Beharkova M, Feherova Z: Influence of selective inhibitors of phosphodiesterase 3 and 4 on cough and airway reactivity. J Physiol Pharmacol. 2008 Dec;59 Suppl 6:473-82. Pubmed
  5. Parkkonen J, Hasala H, Moilanen E, Giembycz MA, Kankaanranta H: Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol. Pulm Pharmacol Ther. 2008;21(3):499-506. Epub 2007 Nov 22. Pubmed

Enzymes

1. 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.
  2. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

2. 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.
  2. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

3. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

4. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

5. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

6. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed

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