CILOSTAZOL — cilostazol tablet
Physicians Total Care, Inc.
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 congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.
Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The empirical formula of cilostazol is C20 H27 N5 O2 , and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1. The structural formula is:
Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
Cilostazol Tablets, USP for oral administration are available as 50 mg or 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch, hypromellose, magnesium stearate and microcrystalline cellulose.
The mechanism of the effects of Cilostazol Tablets, USP on the symptoms of intermittent claudication is not fully understood. Cilostazol Tablets, USP and several of its metabolities are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degration with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Cilostazol Tablets, USP inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Cilostazol Tablets, USP. After 12 weeks, as compared to placebo, Cilostazol Tablets, USP 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (≡ 10%).
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated; the increases were not dose-related.
Cilostazol Tablets, USP 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. 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 Tablets, USP. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about 2-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).
The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of Cilostazol Tablets, USP 100 mg b.i.d. is shown below:
Plasma Concentration Time profile
Plasma Protein and Erythrocyte Binding:
Cilostazol is 95 to 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4′-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
Cilostazol is elminated predominately 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.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 7 times as active as cilostazol), and 4% was 4′-trans-hydroxy-cilostazol (one fifth as active as cilostazol). 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 asother metabolites, non of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
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 across a 50-to-80-year-old age range.
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
The pharmacokinetics of cilostazol and its metabolites were similar with mild hepatic disease as compared to healthy subjects.
Patients with moderate or severe hepatic impairment have not been studied.
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 bindingof the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of patent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 to 98%).
Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions:
Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of Cilostazol Tablets, USP should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).
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