Pharmacology: Pharmacodynamics: The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. 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, respectively.
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogenous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries. Renal arteries are not responsive to the effects of cilostazol.
Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, cilostazol 100 mg twice daily produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4 mg/dL (~10%) compared to placebo.
Pharmacokinetics: Cilostazol is absorbed after oral administration. A high-fat meal increases absorption, with about 90% increase in peak plasma concentration (Cmax) and 25% increase in area under the time-concentration curve (AUC). Absolute bioavailability is unknown.
Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, to a lesser extent, 2C19, and to an even lesser extent, CYP1A2, with metabolites largely excreted in urine. There are two major metabolites, 3,4-dehydro-cilostazol and 4'-trans-hydroxy-cilostazol. The dehydro metabolite is 4 to 7 times as active a platelet antiaggregant as the parent compound and the 4'-trans-hydroxy metabolite is one fifth as active. Plasma concentrations (measured by AUC) of the dehydro and 4'-trans-hydroxy metabolites are ~41% and ~12% of cilostazol concentrations.
Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about two-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
Cilostazol is 95 to 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol and 4'-trans-hydroxy-cilostazol are 97.4% and 66%, respectively.
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%. No evidence of induction of hepatic microenzymes was observed.
Special Populations: Age and Gender: The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender in the 50 to 80 year old range.
Smokers: Smoking decreased cilostazol exposure by about 20% in population pharmacokinetic analysis.
Hepatic Impairment: The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. Patients with moderate or severe hepatic impairment have not been studied.
Renal Impairment: The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of cilostazol and its metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of cilostazol and its metabolites, appeared little changed.
Bioequivalence Study: Cilostazol (Trombocil) 100 mg tablet was shown to be bioequivalent to the reference product (innovator) in adults under fasting conditions. The following are important pharmacokinetic parameters of cilostazol in adult volunteers who received cilostazol (Trombocil) 100 mg tablet (as a single oral dose) under fasting conditions: See table.
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