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  • To date methods for the

    2019-07-05

    To date, methods for the simultaneous analysis of multiple probe drugs in the plasma have been described by using HPLC-DAD or LC–MS/MS. Although previous cocktail methods have used combinations of those four or other probe drugs with LC–MS/MS methods, most of those studies focused on only the analysis of the probe drugs in the plasma and did not measure any metabolites [9,15,16]. In addition, the method published in the literature had the following disadvantages: tedious sample preparation and longer analysis time [7]. Recently, Alexia Grangeona et al. validated an LC–MS/MS method for the determination of major CYP450 isoenzyme activities [17]. The cocktail was composed of caffeine, OME, dextromethorphan and MDZ as the probe drugs for CYP1A2, 2C19, 2D6 and 3A4, respectively. However, this method was complex and based on three different analytical methods. In this study, we established an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the quantification of PHE, OME, MET, MDZ and their metabolites in a single-run process. 3-n-Butylphthalide (NBP) is a pure component of the seed extract from Apium graveolens Linn (Chinese celery) [18]. It was approved by the State Food and Drug Administration (SFDA) of China for the treatment of cerebral ischemia in 2004 [19]. It has been reported that NBP is able to confer neuroprotection through reducing oxidative/nitrosative stress and improving cerebral microvessels with upregulation of the vesicular monoamine transporter 2 gene expression [20]. In addition, NBP is also effective at improving vascular cognitive impairment [21]. In rodents, it prevents neuron damage by ameliorating beta-amyloid-induced neuronal toxicity [22] and inhibiting the JNK-Caspase 3 signaling pathway [23]. Moreover, the absorption, distribution, metabolism and Conoidin A of NBP have been intensively investigated [24]. However, the effect of NBP on the conversion of the probe drugs to metabolites, which is able to reflect CYP450 isoform activities, has not been studied. The present study was designed to develop and validate a rapid, simple and sensitive method for simultaneous determination of ACE/PHE (CYP1A2), OHOME/OME (CYP2C19), OHMET/MET (CYP2D6) and OHMDZ/MDZ (CYP3A4) in rat plasma by UHPLC-MS/MS. Moreover, this developed method investigated the effect of NBP on the metabolic ratio (AUC(0-t), Cmax) of metabolite/probe drugs in rats. To the best of our knowledge, this study was the first to combine the four probe drugs and their main metabolites to evaluate CYP450 enzyme activities.
    Materials and methods
    Results and discussion
    Conclusions
    Acknowledgements This work was supported by the Wenzhou Science and Technology Project (Y20160537) and the Hospital Pharmacy Research Funding Project of Zhejiang Pharmaceutical Association (2016ZYY21).
    Introduction Candida albicans (C. albicans) exist as a normal constituent of the human mucosal microbial ecology. However, inherited or acquired immunodeficiency syndromes in addition to other factors, such as antibiotics, may cause perturbations in the local mucosal immune environment then develop mucosal candida infections and systemic candidiasis due to translocation of yeast from mucosal surfaces into the systemic circulation (Vazquez and Sobel, 2002). The most common forms of mucosal candidiasis are oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) (Smeekens et al., 2013). Human mucosal candidiasis has a substantial global disease burden where, the majority of HIV-infected patients develop oral mucosal candidiasis (de Repentigny et al., 2004). Candidiasis reports declared that approximately 75% of healthy reproductive age women develop at least one episode of VVC during their life time (Sobel, 1997). The largest family of antifungal drugs is azole family that disrupts cell membrane of fungi through inhibiting lanosterol 14-α-demethylase activity (Hof, 2006). Previously, fluconazole has been used extensively for chemoprophylaxis and treatment of systemic fungal infections (Hoffman et al., 2000). Meanwhile, fluconazole resistance has been declared in most of the patients (Redding et al., 2003). Furthermore, some of azole compounds are hepatotoxic, however the specific mechanisms of azole-induced toxicity are not known. Many N-substituted azoles induce and/or inhibit mammalian hepatic cytochrome P450s (Cyps) (Sun et al., 2006). Cyps are responsible for the metabolism of endogenous (steroids) as well as exogenous compounds including drugs and xenobiotic chemicals. This metabolism can lead to metabolic activation to toxic or carcinogenic metabolites. Generally, inhibition of Cyp isoforms can decrease metabolism and hepatic clearance of substrates metabolized by that specific isoform (Kobayashi et al., 2002).