Cilostazol

Identification

Summary

Cilostazol is an antiplatelet agent and vasodilator used for the symptomatic relief of intermittent claudication.

Generic Name
Cilostazol
DrugBank Accession Number
DB01166
Background

Cilostazol is a quinolinone derivative and antiplatelet agent with vasodilating properties that has been used in the symptomatic treatment of intermittent claudication in patients with peripheral ischaemia. It is marketed under the brand name Pletal by Otsuka Pharmaceutical Co.. Cilostazol works by inhibiting both primary and secondary aggregation and reducing calcium-induced contractions.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 369.4607
Monoisotopic: 369.216475133
Chemical Formula
C20H27N5O2
Synonyms
  • 3,4-dihydro-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2(1H)-quinolinone
  • 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone
  • 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydrocarbostyril
  • 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-1H-quinolin-2-one
  • Cilostazol
  • Cilostazole
  • Cilostazolum
External IDs
  • OPC 13013
  • OPC 21
  • OPC-13013
  • OPC-21

Pharmacology

Indication

Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest).

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofIntermittent claudication••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Cilostazol reduces the 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 action

Cilostazol 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.

TargetActionsOrganism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Humans
Absorption

Cilostazol 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 distribution

Not Available

Protein binding

95-98%

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 elimination

Cilostazol 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-life

11-13 hours.

Clearance

Not Available

Adverse Effects
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Toxicity

Information 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.

Pathways
PathwayCategory
Cilostazol Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Cilostazol which could result in a higher serum level.
AbametapirThe serum concentration of Cilostazol can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Cilostazol can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Cilostazol is combined with Abciximab.
AbirateroneThe serum concentration of Cilostazol can be increased when it is combined with Abiraterone.
Food Interactions
  • Avoid grapefruit products.
  • Take on an empty stomach. A high fat meal will increase absorption.

Products

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Product Images
International/Other Brands
Pletaal
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CilostazolTablet50 mg/1OralTEVA PHARMACEUTICALS USA2007-01-082007-01-08US flag
PletalTablet100 mg/1OralPhysicians Total Care, Inc.1999-01-152011-07-31US flag
PletalTablet100 mg/1OralOtsuka Pharmaceutical Co., Ltd.1999-01-152016-06-30US flag
PletalTablet50 mg/1OralPhysicians Total Care, Inc.1999-01-152011-07-31US flag
PletalTablet50 mg/1OralOtsuka Pharmaceutical Co., Ltd.1999-01-152017-11-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CilostazolTablet100 mg/1OralCardinal Health2011-10-182017-01-31US flag
CilostazolTablet100 mg/1OralMylan Institutional2010-02-262013-03-31US flag
CilostazolTablet100 mg/1OralNucare Pharmaceuticals,inc.2004-11-232019-12-31US flag
CilostazolTablet100 mg/1OralNucare Pharmaceuticals,inc.2012-10-24Not applicableUS flag
CilostazolTablet50 mg/1OralSlate Run Pharmaceuticals, Llc2018-01-01Not applicableUS flag

Categories

ATC Codes
B01AC23 — Cilostazol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as hydroquinolones. These are compounds containing a hydrogenated quinoline bearing a ketone group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinolones and derivatives
Direct Parent
Hydroquinolones
Alternative Parents
Hydroquinolines / Alkyl aryl ethers / Benzenoids / Tetrazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Lactams / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds
show 3 more
Substituents
Alkyl aryl ether / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Ether / Heteroaromatic compound
show 12 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tetrazoles, lactam (CHEBI:31401)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
N7Z035406B
CAS number
73963-72-1
InChI Key
RRGUKTPIGVIEKM-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

References

Synthesis Reference

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

US20020099213
General References
Not Available
Human Metabolome Database
HMDB0015297
KEGG Drug
D01896
PubChem Compound
2754
PubChem Substance
46506317
ChemSpider
2652
BindingDB
50225508
RxNav
21107
ChEBI
31401
ChEMBL
CHEMBL799
ZINC
ZINC000001552174
Therapeutic Targets Database
DAP000191
PharmGKB
PA164746334
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cilostazol
MSDS
Download (35.9 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Alphapharm Party Ltd.
  • Apotex Inc.
  • Breckenridge Pharmaceuticals
  • Corepharma LLC
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • Heartland Repack Services LLC
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Otsuka America
  • Physicians Total Care Inc.
  • Prasco Labs
  • Resource Optimization and Innovation LLC
  • Roxane Labs
  • Stat Rx Usa
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Vangard Labs Inc.
Dosage Forms
FormRouteStrength
TabletOral100.000 mg
TabletOral50 mg
TabletConjunctival; Oral100 mg/1
TabletOral100 mg/1
TabletOral100 mg
TabletOral50.000 mg
PowderOral
Tablet
Capsule, extended releaseOral100 MG
Capsule, extended release100 mg
TabletOral
TabletOral50 mg/1
TabletOral100.00 mg
Tablet100 mg
Tablet50 mg
Prices
Unit descriptionCostUnit
Pletal 100 mg tablet2.51USD tablet
Pletal 50 mg tablet2.39USD tablet
Cilostazol 100 mg tablet1.86USD tablet
Cilostazol 50 mg tablet1.86USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)160 °CPhysProp
logP2.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0324 mg/mLALOGPS
logP3.38ALOGPS
logP3.31Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)14.42Chemaxon
pKa (Strongest Basic)-0.67Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area81.93 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity117.13 m3·mol-1Chemaxon
Polarizability41.15 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9909
Caco-2 permeable-0.5666
P-glycoprotein substrateNon-substrate0.5361
P-glycoprotein inhibitor IInhibitor0.7886
P-glycoprotein inhibitor IIInhibitor0.8387
Renal organic cation transporterNon-inhibitor0.5794
CYP450 2C9 substrateNon-substrate0.7887
CYP450 2D6 substrateNon-substrate0.7734
CYP450 3A4 substrateSubstrate0.7407
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9486
Ames testNon AMES toxic0.5436
CarcinogenicityNon-carcinogens0.9085
BiodegradationNot ready biodegradable0.9636
Rat acute toxicity1.9002 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7518
hERG inhibition (predictor II)Non-inhibitor0.7075
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0fal-8947000000-2a45c02fa8163a7e214e
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0fc3-2900000000-aeed8cd6efbb3b93af8e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00dr-1698000000-05ddf5c1a046516bae11
MS/MS Spectrum - , positiveLC-MS/MSsplash10-01t9-3920000000-86a7d65313952e9a8d3f
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0019000000-b3ebf2bfec31d2f1cddd
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-1409000000-3668a1b9926543f0beeb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00el-9027000000-23f547d3ff71afa83553
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014l-1349000000-6e9a9605851ea05be7cf
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fb9-0491000000-6e9856ff8c3e652b5498
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00bm-1952000000-13bd6d2525894ae71a46
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-211.2817102
predicted
DarkChem Lite v0.1.0
[M-H]-211.4616102
predicted
DarkChem Lite v0.1.0
[M-H]-186.14026
predicted
DeepCCS 1.0 (2019)
[M+H]+211.9863102
predicted
DarkChem Lite v0.1.0
[M+H]+211.9354102
predicted
DarkChem Lite v0.1.0
[M+H]+188.49826
predicted
DeepCCS 1.0 (2019)
[M+Na]+211.6461102
predicted
DarkChem Lite v0.1.0
[M+Na]+194.5914
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name
PDE3A
Uniprot ID
Q14432
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight
124978.06 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  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. [Article]
  3. Schror K: The pharmacology of cilostazol. Diabetes Obes Metab. 2002 Mar;4 Suppl 2:S14-9. [Article]
  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. [Article]
  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. doi: 10.1016/j.pupt.2007.11.003. Epub 2007 Nov 22. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
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. [Article]
  2. Cilostazol EMA [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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. [Article]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
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. [Article]
  2. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
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. [Article]
  2. Flockhart Table of Drug Interactions [Link]

Drug created at June 13, 2005 13:24 / Updated at May 07, 2021 21:25