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Pathway Description
Cilostazol Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2019-08-16
Cilostazol, also sold as Pletal, is a drug used to prevent platelet aggregation, specifically treating symptoms of intermittent claudication caused by peripheral artery disease as well as preventing strokes.
Cilostazol is ingested orally, and it enters the liver, where it is metabolized in the endoplasmic reticulum by cytochrome P450 3A4 into 4-hydroxycilostazol, and by cytochrome P450 2C19 and 3A5 into 4-cis-hydroxycilostazol. Each of these metabolites is further metabolized, 4-hydroxycilostazol into 3,4-dehydrocilostazol and 4-cis-hydroxycilostazol into 4'-trans-hydroxycilostazol respectively. These two metabolites are the active metabolites, and they both act to inhibit the action of cAMP-specific 3',5'-cyclic phosphodiesterase 4D in platelets. With this enzyme inhibited, it is unable to metabolize cAMP into AMP, which leads to a buildup of cAMP in the blood. cAMP in turn is known to prevent aggregation of platelets, by inhibiting their adhesion to collagen, as well as decreasing the amount of calcium within the cytosol, preventing granule release, which then prevents activation of other platelets.
References
Cilostazol Pathway References
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Pubmed: 17646278
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Pubmed: 11950794
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Schuetz JD, Schuetz EG, Thottassery JV, Guzelian PS, Strom S, Sun D: Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells. Mol Pharmacol. 1996 Jan;49(1):63-72.
Pubmed: 8569713
Jounaidi Y, Guzelian PS, Maurel P, Vilarem MJ: Sequence of the 5'-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7. Biochem Biophys Res Commun. 1994 Dec 30;205(3):1741-7. doi: 10.1006/bbrc.1994.2870.
Pubmed: 7811260
Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV, et al.: Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 1989 Jun 25;264(18):10388-95.
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Nemoz G, Zhang R, Sette C, Conti M: Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells. FEBS Lett. 1996 Apr 8;384(1):97-102. doi: 10.1016/0014-5793(96)00300-6.
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Bolger GB, McCahill A, Yarwood SJ, Steele MR, Warwicker J, Houslay MD: Delineation of RAID1, the RACK1 interaction domain located within the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5. BMC Biochem. 2002 Aug 23;3:24.
Pubmed: 12193273
Bolger GB, McCahill A, Huston E, Cheung YF, McSorley T, Baillie GS, Houslay MD: The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins. J Biol Chem. 2003 Dec 5;278(49):49230-8. doi: 10.1074/jbc.M303772200. Epub 2003 Sep 18.
Pubmed: 14500724
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