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Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitor.
Pharmacology: Pharmacodynamics: Animal studies have shown Cilostazol to have vasodilator effects and this has been demonstrated in small studies in man where ankle blood flow was measured by strain gauge plethysmography. Cilostazol also inhibits smooth muscle cell proliferation in rat and human smooth muscle cells in vitro, and inhibits the release of platelet-derived growth factor and PF-4 from human platelets.
Studies in animals (in vivo and ex vivo) have shown that Cilostazol causes inhibition of platelet aggregation. The inhibition is effective against a range of aggregants (including shear stress, arachidonic acid, collagen, ADP and adrenaline); in man the inhibition lasts for up to 12 hours, and on cessation of administration of Cilostazol recovery of aggregation occurs within 48-96 hours, without rebound hyperaggregability.
Pharmacokinetics: Absorption: The Cmax of cilostazol and its primary circulating metabolites increase less than proportionally with increasing doses.
However, the AUC for cilostazol and its metabolites increase approximately proportionately with dose.
Distribution: Cilostazol is 95-98% protein bound, predominantly to albumin. The dehydro metabolite and 4'-transhydroxy metabolite are 97.4% and 66% protein bound respectively.
Biotransformation: The apparent elimination half-life of cilostazol is 10.5 hours. There are two major metabolites, a dehydro-cilostazol and a 4'-trans-hydroxy cilostazol, both of which have similar apparent half-lives.
The dehydro metabolite is 4-7 times as active a platelet antiaggregant as the parent compound and the
4'-trans-hydroxymetabolite is one fifth as active. Plasma concentrations (as measured by AUC) of the dehydro and 4'-trans-hydroxy metabolites are ~41% and ~12% of cilostazol concentrations.
Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. The primary isoenzymes involved in its metabolism are cytochrome P-450 CYP3A4, to a lesser extent, CYP2C19, and to an even lesser extent CYP1A2.
Elimination: The primary route of elimination is urinary (74%) with the remainder excreted in the faeces. No measurable amount of unchanged cilostazol is excreted in the urine, and less than 2% of the dose is excreted as the dehydro-cilostazol metabolite. Approximately 30% of the dose is excreted in the urine as the 4'-trans-hydroxy metabolite. The remainder is excreted as metabolites, none of which exceed 5% of the total excreted.
There is no evidence that cilostazol induces hepatic microsomal enzymes.
Older people: The pharmacokinetics of cilostazol and its metabolites were not significantly affected by age or gender in healthy subjects aged between 50-80 years.
In subjects with severe renal impairment, the free fraction of cilostazol was 27% higher and both Cmax and AUC were 29% and 39% lower respectively than in subjects with normal renal function. The Cmax and AUC of the dehydro metabolite were 41% and 47% lower respectively in the severely renally impaired subjects compared to subjects with normal renal function. The Cmax and AUC of 4'-trans-hydroxy cilostazol were 173% and 209% greater in subjects with severe renal impairment. The medicine must not be administered to patients with a creatinine clearance <25ml/min.
Hepatic impairment: There are no data in patients with moderate to severe hepatic impairment and since cilostazol is extensively metabolised by hepatic enzymes, the medicine must not be used in such patients.
