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

Similar Structures

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

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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 Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Symptomatic treatment of	Intermittent 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.

Target	Actions	Organism
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 C_max 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

Pathway	Category
Cilostazol Action Pathway	Drug action

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Cilostazol which could result in a higher serum level.
Abametapir	The serum concentration of Cilostazol can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Cilostazol can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Cilostazol is combined with Abciximab.
Abiraterone	The 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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Cilostazol	Tablet	50 mg/1	Oral	TEVA PHARMACEUTICALS USA	2007-01-08	2007-01-08
Pletal	Tablet	50 mg/1	Oral	Physicians Total Care, Inc.	1999-01-15	2011-07-31
Pletal	Tablet	50 mg/1	Oral	Otsuka Pharmaceutical Co., Ltd.	1999-01-15	2017-11-30
Pletal	Tablet	100 mg/1	Oral	Physicians Total Care, Inc.	1999-01-15	2011-07-31
Pletal	Tablet	100 mg/1	Oral	Otsuka Pharmaceutical Co., Ltd.	1999-01-15	2016-06-30

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Cilostazol	Tablet	50 mg/1	Oral	AvPAK	2016-10-18	Not applicable
Cilostazol	Tablet	100 mg/1	Oral	Stat Rx USA	2006-09-06	Not applicable
Cilostazol	Tablet	100 mg/1	Oral	Lake Erie Medical DBA Quality Care Products LLC	2012-10-24	2015-12-31
Cilostazol	Tablet	50 mg/1	Oral	Carilion Materials Management	2005-05-17	Not applicable
Cilostazol	Tablet	100 mg/1	Conjunctival; Oral	ALHPAPHARM PTY LTD	2010-01-01	2013-01-01

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

External Links

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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Health Services Research	Ischemic Stroke / Peripheral Arterial Disease (PAD) / Type 2 Diabetes Mellitus	1
4	Completed	Other	Intermittent Claudication / Peripheral Arterial Disease (PAD) / Peripheral Vascular Disease Patient	1
4	Completed	Prevention	Cerebral Infarctions	1
4	Completed	Prevention	Noncardioembolic Cerebral Infarction	1
4	Completed	Treatment	Acute Coronary Syndrome (ACS)	1

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

Form	Route	Strength
Tablet	Oral	100.000 mg
Tablet	Oral	50 mg
Tablet	Conjunctival; Oral	100 mg/1
Tablet	Oral	100 mg/1
Tablet	Oral	100 mg
Tablet	Oral	50.000 mg
Powder	Oral
Tablet
Capsule, extended release	Oral	100 MG
Capsule, extended release		100 mg
Tablet	Oral
Tablet	Oral	50 mg/1
Tablet	Oral	100.00 mg
Tablet		100 mg
Tablet		50 mg

Prices

Unit description	Cost	Unit
Pletal 100 mg tablet	2.51USD	tablet
Pletal 50 mg tablet	2.39USD	tablet
Cilostazol 100 mg tablet	1.86USD	tablet
Cilostazol 50 mg tablet	1.86USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	160 °C	PhysProp
logP	2.3	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0324 mg/mL	ALOGPS
logP	3.38	ALOGPS
logP	3.31	Chemaxon
logS	-4.1	ALOGPS
pKa (Strongest Acidic)	14.42	Chemaxon
pKa (Strongest Basic)	-0.67	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	81.93 Å²	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	117.13 m³·mol^-1	Chemaxon
Polarizability	41.15 Å³	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

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 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Non-inhibitor	0.9026
CYP450 3A4 inhibitor	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0fal-8947000000-2a45c02fa8163a7e214e
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	splash10-0fc3-2900000000-aeed8cd6efbb3b93af8e
MS/MS Spectrum - , positive	LC-MS/MS	splash10-00dr-1698000000-05ddf5c1a046516bae11
MS/MS Spectrum - , positive	LC-MS/MS	splash10-01t9-3920000000-86a7d65313952e9a8d3f
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0019000000-b3ebf2bfec31d2f1cddd
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014i-1409000000-3668a1b9926543f0beeb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00el-9027000000-23f547d3ff71afa83553
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014l-1349000000-6e9a9605851ea05be7cf
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0fb9-0491000000-6e9856ff8c3e652b5498
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00bm-1952000000-13bd6d2525894ae71a46
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[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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Details1. cGMP-inhibited 3',5'-cyclic phosphodiesterase A

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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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]
Schror K: The pharmacology of cilostazol. Diabetes Obes Metab. 2002 Mar;4 Suppl 2:S14-9. [Article]
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]
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

Details1. Cytochrome P450 1A2

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

Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. [Article]
Cilostazol EMA [File]

Details2. Cytochrome P450 2D6

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

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

Details3. Cytochrome P450 2C19

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

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

Details4. Cytochrome P450 3A4

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

Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. [Article]
Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Details5. Cytochrome P450 3A5

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

Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. [Article]
Flockhart Table of Drug Interactions [Link]

Details6. Cytochrome P450 3A7

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

Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. [Article]
Flockhart Table of Drug Interactions [Link]

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

Cilostazol

Identification

Structure for Cilostazol (DB01166)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

References

References

References

References

References