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1.
Biol Pharm Bull ; 44(11): 1767-1774, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719653

RESUMO

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.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Infarto Cerebral/tratamento farmacológico , Cilostazol/farmacocinética , Vasodilatadores/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Infarto Cerebral/complicações , Cilostazol/efeitos adversos , Cilostazol/sangue , Cilostazol/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Técnicas de Genotipagem , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Vasodilatadores/efeitos adversos , Vasodilatadores/sangue , Vasodilatadores/uso terapêutico
2.
Artigo em Inglês | MEDLINE | ID: mdl-34247102

RESUMO

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.


Assuntos
Ambroxol/sangue , Cromatografia Líquida/métodos , Cilostazol/sangue , Espectrometria de Massas em Tandem/métodos , Ambroxol/química , Ambroxol/farmacocinética , Animais , Cilostazol/química , Cilostazol/farmacocinética , Interações Medicamentosas , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
3.
Biomed Chromatogr ; 35(10): e5150, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33894005

RESUMO

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.


Assuntos
Cromatografia Líquida/métodos , Cilostazol/análogos & derivados , Cilostazol/sangue , Sistema Enzimático do Citocromo P-450/genética , Espectrometria de Massas em Tandem/métodos , China , Cilostazol/química , Cilostazol/farmacocinética , Genótipo , Humanos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
4.
Eur J Clin Pharmacol ; 74(11): 1417-1426, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30039199

RESUMO

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.


Assuntos
Cilostazol/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Inibidores da Fosfodiesterase 3/farmacocinética , Tetrazóis/sangue , Administração Oral , Adulto , Área Sob a Curva , Povo Asiático/genética , Cromatografia Líquida de Alta Pressão/métodos , Cilostazol/administração & dosagem , Cilostazol/sangue , Genótipo , Humanos , Masculino , Inibidores da Fosfodiesterase 3/administração & dosagem , Polimorfismo Genético , Espectrometria de Massas em Tandem , Adulto Jovem
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