ANALYSIS OF BREFELDIN-A IN PLASMA BY GAS-CHROMATOGRAPHY WITH ELECTRON-CAPTURE DETECTION
ANALYSIS OF BREFELDIN-A IN PLASMA BY GAS-CHROMATOGRAPHY WITH ELECTRON-CAPTURE DETECTION
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DOI：
10.1006/abio.1993.1225
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发表时间：
1993-05-15
影响因子：
2.9
通讯作者：
MALSPEIS, L
中科院分区：
文献类型：
--
作者：
PHILLIPS, LR;SUPKO, JG;MALSPEIS, L
美国国家癌症研究所（NCI）正在进行Brefeldin A（BFA）的临床前开发，Brefeldin A是一种从Brefeldianum青霉菌中分离出来的大环内酯类药物，可作为抗肿瘤药物。BFA对NCI最近建立的体外抗肿瘤筛选中的人肿瘤细胞系具有独特的活性谱。建立了一种测定生物体液中该化合物的方法，即用乙醚从血浆样品中提取BFA和1-二十烷醇作为内标。将通过蒸发有机溶剂得到的残余物真空干燥，并用七氟丁酰咪唑衍生化，然后通过毛细管气相色谱-电子捕获检测进行分析。如质谱法所证实的，BFA的两个仲羟基的衍生化是快速和定量的。在50 μl血浆中，具有可接受重现性的BFA定量最低浓度为0.1 μg/ml，根据不同日期测定的六条标准曲线确定了5.6%的变异系数。对于BFA浓度大于2.5 μg/ml的样品，检测器响应显示出与线性的正偏差。应用表明，该测定法适用于小鼠中BFA血浆药代动力学的初步研究。这些研究表明，BFA从小鼠体内迅速消除，以26.3 mg/kg剂量静脉给药后60 min，血浆水平以明显的双相方式从初始浓度33 μg/ml下降至0.2 μg/ml。
The National Cancer Institute (NCI) is pursuing preclinical development of Brefeldin A (BFA), a macrolide isolated from Penicillium brefeldianum, as an antitumor agent. BFA exhibits a unique spectrum of activity against the human tumor cell line panel that composes the NCI′s recently established in vitro antitumor screen. A specific method to assay the compound in biological fluids has been developed in which BFA and 1-eicosanol, added as the internal standard, are extracted from plasma specimens with diethyl ether. The residue afforded by evaporation of the organic solvent is dried in vacuo and derivatized with heptafluorobutyrylimidazole prior to analysis by capillary gas chromatography with electron capture detection. Derivatization of both secondary hydroxyl groups of BFA is rapid and quantitative, as confirmed by mass spectrometry. The lowest concentration of BFA quantified with acceptable reproducibility in 50 μl of plasma is 0.1 μg/ml, for which a 5.6% coefficient of variation has been determined from six standard curves assayed on separate days. Detector response exhibits a positive deviation from linearity for samples with BFA concentrations greater than 2.5 μg/ml. The assay is shown by application to be suitable for preliminary investigations of BFA plasma pharmacokinetics in mice. These studies reveal that BFA is subject to rapid elimination from the mouse, with plasma levels declining in an apparent biphasic manner from an initial concentration of 33 to 0.2 μg/ml at 60 min after intravenous treatment with a 26.3mg/kg dose.