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Cilostazol

PubChem CID
2754
Structure
Cilostazol_small.png
Cilostazol_3D_Structure.png
Cilostazol__Crystal_Structure.png
Molecular Formula
Synonyms
  • cilostazol
  • 73963-72-1
  • Pletal
  • Cilostazole
  • Pletaal
Molecular Weight
369.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Cilostazol is a lactam that is 3,4-dihydroquinolin-2(1H)-one in which the hydrogen at position 6 is substituted by a 4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy group. It has a role as a bronchodilator agent, a vasodilator agent, a fibrin modulating drug, a platelet aggregation inhibitor, a neuroprotective agent, an anticoagulant and an EC 3.1.4.17 (3',5'-cyclic-nucleotide phosphodiesterase) inhibitor. It is a member of tetrazoles and a lactam.
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.
Cilostazol is a Phosphodiesterase 3 Inhibitor. The mechanism of action of cilostazol is as a Phosphodiesterase 3 Inhibitor.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Cilostazol.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 3
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CCDC Number
Crystal Structure Data
Crystal Structure Depiction
Crystal Structure Depiction

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

6-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RRGUKTPIGVIEKM-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C1CCC(CC1)N2C(=NN=N2)CCCCOC3=CC4=C(C=C3)NC(=O)CC4
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C20H27N5O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 Deprecated CAS

89332-50-3

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone
  • cilostazol
  • OPC 13013
  • OPC-13013
  • Pletal

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
369.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
3.1
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
369.21647512 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
369.21647512 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
81.9 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
27
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
485
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Colorless needle-like crystals from methanol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406

3.2.3 Melting Point

160 °C
PhysProp
159.4-160.3 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406
160 °C

3.2.4 Solubility

Practically insoluble in water
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406
Freely soluble in acetic acid, chloroform, n-methyl-2-pyrrolidone, DMSO; slightly soluble in methanol, ethanol. Practically insoluble in ether. 0.1NHCl, 0.1N NaOH
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406
3.24e-02 g/L

3.2.5 LogP

2.3
2.3

3.2.6 Stability / Shelf Life

Stable under recommended storage conditions.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

3.2.7 Collision Cross Section

199.48 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

194.26 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

181.67 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

195.62 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
199.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breastfeeding; Lactation; Fibrinolytic Agents; Platelet Aggregation Inhibitors;
Human drug -> Prescription; Discontinued; Active ingredient (CILOSTAZOL)
Human drug -> Discontinued

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 MS-MS

1 of 3
View All
Spectra ID
Instrument Type
LC-ESI-qTof
Ionization Mode
Positive
Top 5 Peaks

193.043243 2788

125.016205 2384

97.024185 1460

151.032104 1288

183.05838 1112

Thumbnail
Thumbnail
Notes
From GNPS Library
2 of 3
View All
Spectra ID
Ionization Mode
positive
Top 5 Peaks

370.225769 100

288.147003 72.72

125.083145 19.07

371.226746 18.30

289.148621 9.59

Thumbnail
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Notes
instrument=qTof

4.1.2 LC-MS

MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
370.224
Instrument
qTof
Ionization Mode
positive
Top 5 Peaks

370.225769 100

288.147003 72.72

125.083145 19.07

371.226746 18.30

289.148621 9.59

Thumbnail
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4.2 UV Spectra

UV max (methanol): 257 nm (epsilon 15200)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406

4.3 IR Spectra

4.3.1 FTIR Spectra

Instrument Name
Bruker Tensor 27 FT-IR
Technique
KBr1
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
TCI Chemicals India Pvt. Ltd.
Catalog Number
C2587
Lot Number
QDOPB-OI
Copyright
Copyright © 2015-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.3.2 ATR-IR Spectra

Instrument Name
Bruker Tensor 27 FT-IR
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
TCI Chemicals India Pvt. Ltd.
Catalog Number
C2587
Lot Number
QDOPB-OI
Copyright
Copyright © 2015-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.4 Raman Spectra

Instrument Name
Bruker MultiRAM Stand Alone FT-Raman Spectrometer
Technique
FT-Raman
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
TCI Chemicals India Pvt. Ltd.
Catalog Number
C2587
Lot Number
QDOPB-OI
Copyright
Copyright © 2015-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

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

7.2 LiverTox Summary

Cilostazol is a quinolinone derivative that inhibits specific cellular phosphadiesterases, which cause arterial vasodilation and inhibition of platelet function and makes it a valuable as a therapy of intermittent claudication and as a means of secondary prevention of stroke. Cilostazol has not been associated with serum enzyme elevations during therapy or with published instances of clinically apparent liver injury.

7.3 Drug Classes

Breastfeeding; Lactation; Fibrinolytic Agents; Platelet Aggregation Inhibitors;
Intermittent Claudication Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 Therapeutic Uses

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Cilostazol is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of March 17, 2016: https://clinicaltrials.gov/ct2/results?term=cilostazol&Search=Search
Pletal is indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance. /Included in US product label/
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Because of its antiplatelet activity, cilostazol has been used alone or in combination with other antiplatelet agents (e.g., aspirin, clopidogrel) to prevent thrombosis and restenosis following coronary angioplasty/stent implantation. /NOT included in US product label/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1528
Cilostazol has been used for the secondary prevention of stroke in patients with a history of noncardioembolic stroke or transient ischemic attacks (TIAs). /NOT included in US product label/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1528
/EXPL THER/ We conducted a randomized, double blind, placebo controlled trial to assess the efficacy and safety of cilostazol, a selective inhibitor of phosphodiesterase 3, in patients with vasospastic angina (VSA). Cilostazol has been shown to induce vascular dilatation, but its efficacy in patients with VSA is unknown. Between October 2011 and July 2012, 50 patients with confirmed VSA who had >/= 1 angina episodes/week despite amlodipine therapy (5 mg/day) were randomly assigned to receive either cilostazol (up to 200 mg/day) or placebo for 4 weeks. All patients were given diaries to record the frequency and severity of chest pain (0-10 grading). The primary endpoint was the relative reduction of the weekly incidence of chest pain. Baseline characteristics were similar between the two groups. Among 49 evaluable patients (25 in the cilostazol group, 24 in the placebo group), the primary endpoint was significantly greater in the cilostazol group compared with the placebo group (-66.5 +/- 88.6% vs -17.6 +/- 140.1%, respectively, p=0.009). The secondary endpoints, including a change in the frequency of chest pain (-3.7 +/- 0.5 vs -1.9 +/- 0.6, respectively, p=0.029), a change in the chest pain severity scale (-2.8 +/- 0.4 vs -1.1 +/- 0.4, respectively, p=0.003), and the proportion of chest pain-free patients (76.0% vs 33.3%, respectively, p=0.003) also significantly favoured cilostazol. Headache was the most common adverse event in both groups (40.0% vs 20.8%, respectively, p=0.217). Cilostazol is an effective therapy for patients with VSA uncontrolled by conventional amlodipine therapy, and has no serious side effects.
Shin ES et al; Heart 100 (19): 1531-6 (2014)

7.10 Drug Warnings

/BOXED WARNING/ WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS. Pletal is contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis have been reported when cilostazol was not immediately discontinued; agranulocytosis was reversible with discontinuance of cilostazol.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Information is limited regarding the safety and efficacy of concurrent use of cilostazol and clopidogrel. Currently it is unknown whether concurrent therapy with cilostazol and clopidogrel has additive effects on bleeding time. Caution should be used and bleeding times monitored during such concurrent therapy.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
For more Drug Warnings (Complete) data for Cilostazol (10 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 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.

8.2 MeSH Pharmacological Classification

Fibrinolytic Agents
Fibrinolysin or agents that convert plasminogen to FIBRINOLYSIN. (See all compounds classified as Fibrinolytic Agents.)
Neuroprotective Agents
Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. (See all compounds classified as Neuroprotective Agents.)
Vasodilator Agents
Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)
Platelet Aggregation Inhibitors
Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. (See all compounds classified as Platelet Aggregation Inhibitors.)
Phosphodiesterase 3 Inhibitors
Compounds that specifically inhibit PHOSPHODIESTERASE 3. (See all compounds classified as Phosphodiesterase 3 Inhibitors.)
Bronchodilator Agents
Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
N7Z035406B
Active Moiety
CILOSTAZOL
Pharmacological Classes
Established Pharmacologic Class [EPC] - Phosphodiesterase 3 Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Phosphodiesterase 3 Inhibitors
FDA Pharmacology Summary
Cilostazol is a Phosphodiesterase 3 Inhibitor. The mechanism of action of cilostazol is as a Phosphodiesterase 3 Inhibitor.
2 of 2
Non-Proprietary Name
CILOSTAZOL
Pharmacological Classes
Phosphodiesterase 3 Inhibitors [MoA]; Phosphodiesterase 3 Inhibitor [EPC]

8.4 ATC Code

B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AC - Platelet aggregation inhibitors excl. heparin

B01AC23 - Cilostazol

8.5 Absorption, Distribution and Excretion

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.
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.
/MILK/ Transfer of cilostazol into milk has been reported in rats.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Following oral administration of a single 100-mg dose of cilostazol with a high-fat meal, peak plasma cilostazol concentrations and area under the plasma concentration-time curve (AUC) increased by approximately 90 and 25%, respectively.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Pletal 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.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
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. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of /microsomal enzymes/.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
For more Absorption, Distribution and Excretion (Complete) data for Cilostazol (7 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

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.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4'-trans-hydroxy-cilostazol (20% as active as cilostazol).
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
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 Pletal.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentration-time curve (AUC) was about 35-fold higher in female rats than in male rats, and absolute bioavailability was about 5.8-fold higher in female rats than in male rats. Total body clearance (CL(total)) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CL(h)) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CL(total) of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats. In vitro metabolism studies utilizing hepatic microsomes and recombinant cytochrome (CYP) isoforms clearly indicated that major metabolites of cilostazol were generated extensively with hepatic microsomes of male rats and that male-predominant CYP3A2 and male-specific CYP2C11 were mainly responsible for the hepatic metabolism of cilostazol. Therefore, the great sex differences in the pharmacokinetics of cilostazol were mainly attributed to the large difference in hepatic metabolism. Our experimental results also suggested that the substantial metabolism of cilostazol in the small intestine and its possible saturation would be responsible for dose-dependent bioavailability in both male and female rats.
Kamada N et al; Xenobiotica 41 (10): 903-13 (2011)
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. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of /microsomal enzymes/.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Cilostazol has known human metabolites that include OPC-13217 and OPC-13326.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.7 Biological Half-Life

11-13 hours.
Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 25, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b

8.8 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.
Cilostazol, a phosphodiesterase 3, has been widely used in patients with arterial disease and is known to have additional beneficial effects on dyslipidemia. However, the effect of cilostazol on hepatic steatosis has not been fully elucidated. We investigated the effect of cilostazol on hepatic ABCA1 expression and hepatic steatosis in diet-induced obesity mice model. Hepatic ABCA1 expression and lipid accumulation were analyzed in HepG2 cell lines treated with cilostazol. Male C57BL/6 mice were randomly divided into three groups: (1) fed normal chow diet with vehicle; (2) fed high-fat diet (HFD) with vehicle; (3) fed HFD with cilostazol. Cilostazol (30 mg/kg) was orally administered once daily for 9 weeks. Cilostazol significantly enhanced ABCA1 expression and restored ABCA1 expression reduced by palmitate in HepG2 cells. Cilostazol treatment ameliorated lipid accumulation induced by palmitate, and this effect was diminished when ABCA1 or LRP1 was silenced by small interference RNA. After silencing of LRP1, ABCA1 expression was decreased in HepG2 cells. Cilostazol significantly enhanced hepatic ABCA1 expression and decreased hepatic fat in HFD-fed mice. Hepatic expression of cleaved caspase-3 and PARP1 was also decreased in HFD-fed mice treated with cilostazol. Cilostazol ameliorated hepatic steatosis and increased ABCA1 expression in the hepatocytes. Enhancing ABCA1 expression with cilostazol represents a potential therapeutic avenue for treatment of hepatic steatosis.
Jeon BH et al; Metabolism 64 (11): 1444-53 (2015)
Cilostazol, a quinolinone-derivative selective phosphodiesterase (PDE) inhibitor, is a platelet-aggregation inhibitor and arterial vasodilator. Although the mechanism of action of cilostazol has not been fully elucidated, the drug appears to inhibit activation of cellular PDE type III (PDE III), resulting in suppressed degradation, and thus increased concentrations, of cyclic adenosine-3',5'-monophosphate (cAMP) in platelets and blood vessels. Increased cAMP concentrations are thought to result in arterial vasodilation and inhibition of platelet aggregation.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

8.9.2 Metabolite Pathways

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

MEDICATION

Use (kg; approx.) in Germany (2009): >1000

Consumption (g per capita; approx.) in Germany (2009): 0.0122

Calculated removal (%): 49

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

Preparation: Belgium patent 878548; T. Nishi, K. Nakagawa, United States of America patent 4277479 (1979, 1981 both to Otsuka).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406

9.3 Formulations / Preparations

Table: Cilostazol Preparations
Route of Administration
Oral
Dosage Form
Tablets
Strength
50 mg
Brand or Generic Form (Manufacturer)
Cilostazol Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
50 mg
Brand or Generic Form (Manufacturer)
Pletal (Otsuka)
Route of Administration
Oral
Dosage Form
Tablets
Strength
100 mg
Brand or Generic Form (Manufacturer)
Cilostazol Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
100 mg
Brand or Generic Form (Manufacturer)
Pletal (Otsuka)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1530

10 Identification

10.1 Clinical Laboratory Methods

HPLC determination in plasma.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 406

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Health Hazard
Signal
Warning
GHS Hazard Statements
H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]
Precautionary Statement Codes

P203, P280, P318, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Repr. 2 (100%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.3 Preventive Measures

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: General industrial hygiene practice.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

11.4 Handling and Storage

11.4.1 Storage Conditions

Store Pletal tablets at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Keep container tightly closed in a dry and well-ventilated place.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

11.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including cilostazol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 23, 2016: https://www.fda.gov/cder/ob/

11.8 Other Safety Information

11.8.1 Toxic Combustion Products

Special hazards arising from the substance or mixture: Carbon oxides, Nitrogen oxides (NOx)
Sigma-Aldrich; Safety Data Sheet for Cilostazol. Product Number: C0737, Version 3.8 (Revision Date 08/21/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Cilostazol forms colorless, needle-like crystals. As the oral drug Pletal, it is indicated for the reduction of symptoms of intermittent claudication. HUMAN EXPOSURE AND TOXICITY: The signs and symptoms of an acute overdose may include severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. ANIMAL STUDIES: No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the maximum recommended human dose (MRHD). Repeated oral administration of cilostazol to dogs produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, AUC to unbound cilostazol was less than that seen in humans at the MRHD of 100 mg twice daily. In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay. Dietary administration of cilostazol to rats and mice for up to 104 weeks revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug.

12.1.2 Hepatotoxicity

In publications of the multiple, large prospective trials of cilostazol therapy, rates of serum ALT elevations during therapy were not provided. Furthermore, there were no reported instances of clinically apparent acute liver injury. Since its approval and wide scale use, there have been no published reports of hepatotoxicity attributed to cilostazol. Nevertheless, the current product label mentions that instances of serum enzyme elevations and hepatitis have been reported to the sponsor. The time of onset, clinical pattern and course of liver test abnormalities during cilostazol therapy have not been reported.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
cilostazol
DILI Annotation
Ambiguous DILI-concern
Severity Grade
5
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Because no information is available on the use of cilostazol during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.5 Acute Effects

12.1.6 Interactions

Pharmacokinetic interaction (increased plasma concentrations of active metabolite 3,4-dehydro-cilostazol) with CYP2C19 inhibitors, including omeprazole; use with caution and consider reduced dosage.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Potential pharmacokinetic interaction (increased plasma lovastatin concentrations and decreased plasma cilostazol concentration) with lovastatin, a substrate for CYP3A4, although unlikely to be clinically important.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Pharmacokinetic interaction (increased plasma cilostazol concentrations); use with caution and consider reduced dosage. Potential pharmacokinetic interaction (increased plasma cilostazol concentrations, decreased clearance) with other inhibitors of CYP3A4 isoenzyme, including, but not limited to, certain azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole), certain macrolide antibiotics (e.g., erythromycin or clarithromycin but not azithromycin), certain selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, nefazodone, sertraline), certain antiretroviral agents (e.g., indinavir), metronidazole, diltiazem, and danazol.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
Potentially additive antiplatelet effects with clopidogrel and cilostazol. Caution is advised and bleeding times should be monitored during such concomitant therapy. Pharmacokinetic interaction unlikely.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 1529
For more Interactions (Complete) data for Cilostazol (10 total), please visit the HSDB record page.

12.1.7 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1

12.1.8 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
/SIGNS AND SYMPTOMS/ 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.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
/CASE REPORTS/ Cilostazol, a phosphodiesterase III inhibitor, is known to increase the heart rate; however, its effects on glucose metabolism remain unclear. We observed that the blood glucose level varied in parallel with the heart rate immediately after starting or stopping cilostazol therapy in three patients with type 2 diabetes. This finding indicates that cilostazol induces hyperglycemia and tachycardia in a portion of diabetic patients, presumably via similar pharmacological effects on different organs. Much more attention should be paid to the possible effects of cilostazol on glycemic control, including taking into consideration the risk-benefit ratio of cilostazol use and individual circumstances.
Aoki Y et al; Intern Med 53 (8): 859-63 (2014)
/ALTERNATIVE and IN VITRO TESTS/ Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells. Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) gamma, and phospholipase C (PLC) e, suppressed cilostazol-induced PGI2 synthesis. The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCe/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kgamma, resulting in synergistically induced PGI2 synthesis.
Hashimoto A et al; PLoS One 10 (7): e0132835 (2015)
For more Human Toxicity Excerpts (Complete) data for Cilostazol (8 total), please visit the HSDB record page.

12.1.9 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Cardiovascular lesions were ... not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the maximum recommended human dose (MRHD).
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2 weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats.
Tani T et al; Atherosclerosis 152 (2): 299-305 (2000)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg twice daily. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
For more Non-Human Toxicity Excerpts (Complete) data for Cilostazol (15 total), please visit the HSDB record page.

12.1.10 Non-Human Toxicity Values

LD50 Dog oral > 2 g/kg
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
LD50 Rat oral > 5 g/kg
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
LD50 Mouse oral > 5 g/kg
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b

12.1.11 Ongoing Test Status

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 17, 2015: http://actor.epa.gov/dashboard/]

12.1.12 Populations at Special Risk

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS. Pletal is contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b
Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.
NIH; DailyMed. Current Medication Information for Pletal (Cilostazol) Tablet (Updated: July 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d75b58-bafb-4440-b8d7-4f4079c08b0b

12.1.13 Protein Binding

95-98%

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

  • Avoid grapefruit products.
  • Take on an empty stomach. A high fat meal will increase absorption.

16.4 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: Drug

18.5 KEGG: USP

18.6 KEGG: ATC

18.7 KEGG: Target-based Classification of Drugs

18.8 KEGG: JP15

18.9 KEGG: Drug Groups

18.10 WHO ATC Classification System

18.11 FDA Pharm Classes

18.12 ChemIDplus

18.13 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.14 ChEMBL Target Tree

18.15 UN GHS Classification

18.16 NORMAN Suspect List Exchange Classification

18.17 CCSBase Classification

18.18 EPA DSSTox Classification

18.19 FDA Drug Type and Pharmacologic Classification

18.20 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  5. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    6-[4-(1-cyclohexyl-1H-1,2,3,4-tetrazol-5-yl)butoxy]-1,2,3,4-tetrahydroquinolin-2-one
    https://echa.europa.eu/substance-information/-/substanceinfo/100.215.897
    6-[4-(1-cyclohexyl-1H-1,2,3,4-tetrazol-5-yl)butoxy]-1,2,3,4-tetrahydroquinolin-2-one (EC: 689-122-9)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/221151
  7. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  8. Hazardous Substances Data Bank (HSDB)
  9. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  10. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  11. ChEBI
  12. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. LiverTox
  14. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  15. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  16. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  17. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  18. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  19. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  20. Therapeutic Target Database (TTD)
  21. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  22. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  23. The Cambridge Structural Database
  24. DailyMed
  25. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  26. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    CILOSTAZOL
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  27. Drugs and Lactation Database (LactMed)
  28. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. EU Clinical Trials Register
  30. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  31. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. Japan Chemical Substance Dictionary (Nikkaji)
  33. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Drugs listed in the Japanese Pharmacopoeia
    http://www.genome.jp/kegg-bin/get_htext?br08311.keg
  34. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  35. Metabolomics Workbench
  36. NIPH Clinical Trials Search of Japan
  37. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  38. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  39. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  40. SpectraBase
  41. Springer Nature
  42. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  43. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  44. Wikidata
  45. Wikipedia
  46. Wiley
  47. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Platelet Aggregation Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68010975
    Phosphodiesterase 3 Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68058987
  48. PubChem
  49. GHS Classification (UNECE)
  50. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  51. PATENTSCOPE (WIPO)
  52. NCBI
CONTENTS