Update on Cilostazol: A Critical Review of Its Antithrombotic and Cardiovascular Actions and Its Clinical Applications.

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated.

Impact of Cilostazol Pharmacokinetics on the Development of Cardiovascular Side Effects in Patients with Cerebral Infarction.

This study investigated the impact of polymorphisms of metabolic enzymes on plasma concentrations of cilostazol and its metabolites, and the influence of the plasma concentrations and polymorphisms on the cardiovascular side effects in 30 patients with cerebral infarction. Plasma concentrations of cilostazol and its active metabolites, and CYP3A5*3 and CYP2C19*2 and *3 genotypes were determined. The median plasma concentration/dose ratio of OPC-13213, an active metabolite by CYP3A5 and CYP2C19, was slightly higher and the median plasma concentration rate of cilostazol to OPC-13015, another active metabolite by CYP3A4, was significantly lower in CYP3A5*1 carriers than in *1 non-carriers (p = 0.082 and p = 0.002, respectively). The CYP2C19 genotype did not affect the pharmacokinetics of cilostazol. A correlation was observed between changes in pulse rate from the baseline and plasma concentrations of cilostazol (R = 0.539, p = 0.002), OPC-13015 (R = 0.396, p = 0.030) and OPC-13213 (R = 0.383, p = 0.037). A multiple regression model, consisting of factors of the plasma concentration of OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of the therapy explained 55.5% of the interindividual variability of the changes in pulse rate. These results suggest that plasma concentrations of cilostazol and its metabolites are affected by CYP3A5 genotypes, and plasma concentration of OPC-13015, blood urea nitrogen, and pulse rate at the start of therapy may be predictive markers of cardiovascular side effects of cilostazol in patients with cerebral infarction.

A simple LC-MS/MS method for simultaneous determination of cilostazol and ambroxol in Sprague-Dawley rat plasma and its application to drug-drug pharmacokinetic interaction study following oral delivery in rats.

Recently, a combination of cilostazol and ambroxol has been used in the clinical treatment of stroke-associated pneumonia (SAP). However, the pharmacokinetic drug-drug interaction (DDI) of cilostazol and ambroxol has not been reported. In this paper, a rapid, reproducible and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of cilostazol and ambroxol in Sprague-Dawley (SD) rat plasma was established and validated for the first time. Domperidone was used as the internal standard (IS) and one-step liquid-liquid extraction (LLE) method was used to extract analytes and IS from plasma samples with methyl tert-butyl ether as extractant. A rapid chromatographic separation within 4.8 min was carried on an Ultimate ® XB-C18 column with a mobile phase consisting of methanol-acetonitrile-formic acid (0.1%) aqueous solution (90:2:8, v/v/v) at a flow rate of 500 µL/min. The quantitative detection of the analytes and IS were performed on a positive electrospray ionization mode (ESI), and scanned by multi-reaction monitoring (MRM) with the ion transitions m/z 370.3 â†’ m/z 288.2 for cilostazol, m/z 378.8 â†’ m/z 263.8 for ambroxol and m/z 426.2 â†’ m/z 175.1 for domperidone (IS), respectively. It had good linearity in the range of 5.0-1000 ng/mL for cilostazol and 1.0-200 ng/mL for ambroxol in rat plasma. The methodology was fully validated with selectivity, linearity, lower limits of quantification, precision, accuracy, extraction recovery, matrix effect, stability and carry-over effect. The validated data have met the determination requirements of biological samples in FDA guideline. The method was successfully applied to the pharmacokinetics and DDI study of cilostazol and ambroxol in male SD rats. The current study found that the interaction between cilostazol and ambroxol may be caused by CYP3A4 and the pharmacological properties of cilostazol, which may be helpful for therapeutic drug monitoring, clinical dose reference and provide a valuable tool for drug-drug interactions.

A new simple method for quantification of cilostazol and its active metabolite in human plasma by LC-MS/MS: Application to pharmacokinetics of cilostazol associated with CYP genotypes in healthy Chinese population.

A simple, sensitive, and fully automated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of cilostazol (CIL) and its active metabolite, 3,4-dehydro cilostazol (CIL-M), in human plasma. Plasma samples were processed by protein precipitation in 2 mL 96-deep-well plates, and all liquid transfer steps were performed through robotic liquid handling workstation, enabling the whole procedure fast, compared to the reported methods. Separation of analytes was successfully achieved on a UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) with mobile phase A (5 mM ammonium formate containing 0.1% formic acid) and mobile phase B (methanol) at a flow rate of 0.30 mL min-1 . The total run time was 3.5 min per sample. Mass spectrometric detection was conducted by electrospray ion source in positive ion multiple reaction monitoring mode. Calibration curves were linear over the concentration range of 1.0-800 ng·mL-1 for CIL and 0.05-400 ng·mL-1 for CIL-M. The coefficient of variation for the assay's precision was 12.3%, and the accuracy was 88.8-99.8%. It was fully validated and successfully applied to assess the influence of CYP genotypes on the pharmacokinetics of CIL after oral administration of 50 mg tablet formulations of CIL to healthy Chinese volunteers. The results suggest that, in Chinese population, the genotype of CYP3A5 affects the plasma exposure of CIL.

Food effect on meal administration time of pharmacokinetic profile of cilostazol, a BCS class II drug.

Cilostazol (CLZ) is categorized as a biopharmaceutical classification system (BCS) class II drug. CLZ suspensions of jet-milled particles were orally administered to beagle dogs in fasted and fed states, for which food was given 0.5 h before the experiment.The mean highest concentration of CLZ (Cmax) and the area under the serum concentration-time curve (AUCt) fed/fasted ratios were 2.90 and 2.85, respectively, indicating a large and variable food effect. Additionally, CLZ was administered to the same dogs at 2 and 4 h after food or 0.5 h before food. The serum concentrations of CLZ were similar when dosed 0.5 and 2 h after food; however, they were significantly lower when dosed 4 h after food but still greater compared with the fasted state.Furthermore, the ratio of fed/fasted in AUCt was better correlated than that in Cmax. Additionally, the serum concentrations were similar to the fasted states when CLZ was dosed 0.5 h before food.Therefore, the results of this study showed that the serum concentration-time profile of CLZ was significantly affected by the timing of food administration, and that a good correlation was observed between food administration time and the Cmax and AUCt fed/fasted ratios.

Evaluation of Pharmacokinetic Interaction of Cilostazol with Metoclopramide after Oral Administration in Human.

BACKGROUND: Metoclopramide is mainly metabolized by CYP2D6, CYP3A4, CYP2C19, and CYP1A2 enzymes, while cilostazol is also metabolized by CYP3A4, CYP2C19, and CYP1A2 enzymes. AIM: This study evaluates the effect of cilostazol on the pharmacokinetics of oral metoclopramide. METHODS: This was a randomized, two-phase cross-over pharmacokinetic study separated by a 4-week wash-out time period, 12 healthy non-smoking volunteers received metoclopramide 20 mg as a single oral dose and after 4 weeks, cilostazol 100 mg twice daily for 4 days then with metoclopramide 20 mg on test day. Serial blood samples were analyzed by using a validated high-performance liquid chromatography-ultraviolet method to determine maximum plasma drug concentration (Cmax), time to reach (Tmax), and area under the curve (AUC0-∞) of metoclopramide. RESULTS: Cilostazol increased the mean Cmax, AUC0-∞ and half-life (T1/2) of metoclopramide by 6%, 27% and by 0.79 %, respectively. In addition, Tmax of metoclopramide was delayed by cilostazol. CONCLUSION: The results showed delayed Tmax of metoclopramide by cilostazol, which could lead to the conclusion that cilostazol affects the absorption of metoclopramide. Both drugs when necessary to administer together must not be administered at the same time especially when given in gastroparesis patients.

Pharmacokinetic study of two extended-release formulations of cilostazol in healthy Korean subjects: A randomized, open-label, multiple-dose, two-period crossover study
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OBJECTIVES: The aim of this study was to compare the pharmacokinetic characteristics and safety of two extended-release formulations of cilostazol after multiple oral doses in healthy Korean subjects. MATERIALS AND METHODS: A randomized, open-label, multiple-dose, two-period, crossover study was conducted in 30 healthy male subjects. In each treatment period, subjects received oral doses of 200 mg cilostazol SR (Pletaal SR Cap.) or cilostazol CR (Cilostan CR Tab.) once daily for 5 consecutive days, with a washout period of 9 days. Plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: 24 subjects completed the study. The maximum plasma concentrations (Cmax,ss, geometric mean (geometric coefficient of variation, CV%)) of cilostazol after cilostazol SR and cilostazol CR regimens were 1,532.7 (43.2%) ng/mL and 548.3 (58.9%) ng/mL, respectively, and the areas under the plasma concentration-time curves within dosing intervals (AUCτ, geometric mean (CV%)) were 17,060.7 (39.2%) h×ng/mL and 7,485.7 (55.0%) h×ng/mL, respectively. The geometric mean ratios (cilostazol SR/cilostazol CR) of the Cmax,ss and AUCτ values were 2.7954 (90% confidence interval: 2.3561 - 3.3166) and 2.2791 (90% confidence interval: 1.9770 - 2.6273), respectively. Both cilostazol SR and cilostazol CR were well tolerated in all subjects, and no serious adverse events occurred. The total incidence of headache, which is the most common adverse drug reaction, was significantly higher with cilostazol SR (63.0%) than cilostazol CR (25.9%). CONCLUSION: Cilostazol SR showed significantly higher Cmax and AUCτ of cilostazol than cilostazol CR after 5 days of multiple dosing of extended-release formulations of cilostazol.

Double controlled release of highly insoluble cilostazol using surfactant-driven pH dependent and pH-independent polymeric blends and in vivo bioavailability in beagle dogs.

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol-gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol-gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.

Effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its active metabolites.

PURPOSE: CYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites. METHODS: Thirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS. RESULTS: Although the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC0-∞ for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype. CONCLUSION: These results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.

Cilostazol-Loaded Poly(ε-Caprolactone) Electrospun Drug Delivery System for Cardiovascular Applications.

PURPOSE: The study discusses the value of electrospun cilostazol-loaded (CIL) polymer structures for potential vascular implant applications. METHODS: Biodegradable polycaprolactone (PCL) fibers were produced by electrospinning on a rotating drum collector. Three different concentrations of CIL: 6.25%, 12.50% and 18.75% based on the amount of polymer, were incorporated into the fibers. The fibers were characterized by their size, shape and orientation. Materials characterization was carried out by Fourier Transformed Infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vitro drug release study was conducted using flow-through cell apparatus (USP 4). RESULTS: Three-dimensional structures characterized by fibers diameter ranging from 0.81 to 2.48 µm were in the range required for cardiovascular application. DSC and XRD confirmed the presence of CIL in the electrospun fibers. FTIR and Raman spectra confirmed CIL polymorphic form. Elastic modulus values for PCL and the CIL-loaded PCL fibers were in the range from 0.6 to 1.1 GPa. The in vitro release studies were conducted and revealed drug dissolution in combination with diffusion and polymer relaxation as mechanisms for CIL release from the polymer matrix. CONCLUSIONS: The release profile of CIL and nanomechanical properties of all formulations of PCL fibers demonstrate that the cilostazol loaded PCL fibers are an efficient delivery system for vascular implant application.