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Identification
Name Cilostazol
Accession Number DB01166 (APRD00155)
Type small molecule
Groups approved
Description

Cilostazol is a medication used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. It is manufactured by Otsuka Pharmaceutical Co. under the trade name Pletal. Although drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure, studies of significant size have not addressed people without the disease. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Cilostazole
Cilostazolum [INN-Latin]
Salts Not Available
Brand names
Name Company
Pletaal
Pletal
Brand mixtures Not Available
Categories
  • Vasodilator Agents
  • Platelet Aggregation Inhibitors
  • Fibrinolytic Agents
  • Phosphodiesterase Inhibitors
  • Bronchodilator Agents
  • Neuroprotective Agents
CAS number 73963-72-1
Weight Average: 369.4607
Monoisotopic: 369.216475133
Chemical Formula C20H27N5O2
InChI Key InChIKey=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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Quinolinones
  • Phenylpropylamines
  • (Iso)quinolines and Derivatives
  • Lactams
Substructures
  • Phenols and Derivatives
  • Amino Ketones
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Tetrazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Quinolinones
  • Anisoles
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • (Iso)quinolines and Derivatives
  • Lactams
  • Imines
  • Cyanamides
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For the reduction of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest).
Pharmacodynamics Cilostazol is a quinolinone derivative indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs.
Mechanism of 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.
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
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.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00263 Cilostazol Pathway SMP00263
Pharmacoeconomics
Manufacturers
  • Actavis totowa llc
  • Alphapharm party ltd
  • Apotex inc etobicoke site
  • Breckenridge pharmaceutical inc
  • Corepharma llc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Pliva hrvatska doo
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Otsuka pharmaceutical co ltd
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Pletal 100 mg tablet 2.51 USD tablet
Pletal 50 mg tablet 2.39 USD tablet
Cilostazol 100 mg tablet 1.86 USD tablet
Cilostazol 50 mg tablet 1.86 USD 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 160 °C PhysProp
logP 2.3 Not Available
Predicted Properties
Property Value Source
water solubility 3.24e-02 g/l ALOGPS
logP 3.38 ALOGPS
logP 3.31 ChemAxon
logS -4.1 ALOGPS
pKa (strongest acidic) 14.42 ChemAxon
pKa (strongest basic) -0.51 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 81.93 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 117.13 ChemAxon
polarizability 41.15 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01896 Link_out
PubChem Compound 2754 Link_out
PubChem Substance 46506317 Link_out
ChemSpider 2652 Link_out
BindingDB 50070490 Link_out
ChEBI 31401 Link_out
ChEMBL 31401 Link_out
Therapeutic Targets Database DAP000191 Link_out
PharmGKB PA164746334 Link_out
RxList http://www.rxlist.com/cgi/generic/cilostaz.htm Link_out
Drugs.com http://www.drugs.com/cdi/cilostazol.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Cilostazol Link_out
ATC Codes
  • B01AC23
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (35.9 KB)
Interactions
Drug Interactions
Drug Interaction
Diltiazem Diltiazem, a moderate CYP3A4 inhibitor, may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cilostazol if diltiazem is initiated, discontinued or dose changed.
Erythromycin Erythromycin increases the effect of cilostazol
Fluconazole Fluconazole may decrease the effect of cilostazol.
Fluoxetine Fluoxetine, a moderate CYP2C19 inhibitor, may decrease the metabolism of cilostazol. Monitor for changes in the therapeutic and adverse effects of cilostazol if fluoxetine is initiated, discontinued or dose changed.
Fluvoxamine Fluvoxamine increases the effect of cilostazol
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Itraconazole Itraconazole may increase the effect of cilostazol.
Josamycin Erythromycin increases the effect of cilostazol
Ketoconazole Ketoconazole may increase the effect of cilostazol.
Nefazodone Nefazodone increases the effect of cilostazol
Omeprazole Omeprazole increases the effect of cilostazol
Sertraline Sertraline increases the effect of cilostazol
Telithromycin Telithromycin may reduce clearance of Cilostazol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Cilostazol if Telithromycin is initiated, discontinued or dose changed.
Ticlopidine Ticlopidine may decrease the metabolism and clearance of Cilostazol. Consider alternate therapy or monitor for adverse/toxic effects of Cilostazol if Ticlopidine is initiated, discontinued or dose changed.
Treprostinil The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Cilostazol. Monitor for increased bleeding during concomitant thearpy.
Voriconazole Voriconzole may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for increased therapeutic/adverse effects of cilostazol and consider reducing the dose during concomitant therapy.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment, grapefruit can significantly increase serum levels of this product.
  • Take on an empty stomach, a lipid rich meal will increase absorption.
Targets

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

Pharmacological action: yes
Actions: inhibitor

Hydrolyzes both cyclic AMP (cAMP) and cyclic GMP (cGMP)

Organism class: human
UniProt ID: Q14432 Link_out
Gene: PDE3A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

1. Cytochrome P450 3A5

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Cytochrome P450 3A7

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. Cytochrome P450 2C19

Actions: substrate

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 imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

4. Cytochrome P450 3A4

Actions: substrate

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

5. Cytochrome P450 1A2

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

6. Cytochrome P450 2D6

Actions: substrate

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 antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19