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首页> 外文会议>ASMS Conference on Mass Spectrometry and Allied Topics >Ultra-sensitive quantification of corticosteroids in plasma samples using selective solid phase extraction and reversed-phase capillary high performance liquid chromatography/tandem mass spectrometry
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Ultra-sensitive quantification of corticosteroids in plasma samples using selective solid phase extraction and reversed-phase capillary high performance liquid chromatography/tandem mass spectrometry

机译：使用选择性固相萃取和反相毛细管高效液相色谱/串联质谱法的血浆样品中皮质类固醇的超敏定量

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Low-dose corticosteroids may provide a favorable benefit/risk ratio for many therapeutic applications. However, the extremely low plasma drug concentrations achieved, in conjunction with the insufficient sensitivity/selectivity of current analytical methods, renders the evaluation of corticosteroid pharmacokinetics (PK) a significant challenge under such conditions. Furthermore, targeted therapeutic strategies involving administration by inhalation or intraocular injection could result in very low but sustained systemic corticosteroid concentrations, which must be quantified to determine potential side effects. Here we describe a robust method for the ultra-sensitive quantification of corticosteroids in plasma samples. This was achieved by the combination of a selective solid phase extraction (SPE) with a highly-sensitive capillary LC ((mu)LC)-MS/MS analysis. SPE washing and elution conditions were optimized so that target drugs are selectively extracted from plasma. By eliminating most undesirable compounds from the sample matrix, this selective SPE procedure enabled a high sample loading volume on the (mu)LC column without compromising chromatographic performance and operational robustness, and helped to achieve ultra-low detection limits for the corticosteroids in plasma. The effect of (mu)LC separation on the signal-to-noise ratio of corticosteroid peaks in plasma samples was investigated. It was found that with sufficient (mu)LC separation, sensitivity was improved because of a decrease in matrix effects and the removal of endogenous interferences. Detection limits of four clinically-important corticosteroids (budesonide, dexamethasone, triamcinolone acetonide, and dexamethasone acetate) ranged from 0.2-1 pg/mL in plasma, and linearity was good for all drugs in the range of 5-5,000 pg/mL. Accuracy was 88-107percent and the variation (CV(percent)) was 2.3-11.1percent. A limit of quantification (LOQ) of 5 pg/mL was validated for all 4 compounds. We applied this method to quantify the low levels of triamcinolone acetonide (TACA) in porcine plasma following suprachoroidal administration, which is necessary to estimate systemic drug exposure resulting from this novel clinical approach for treating inflammatory diseases of the eye. TACA in plasma could be quantified at low pg/mL levels for up to 90 days post-treatment. To our knowledge, this is the first practical analytical approach that can monitor plasma corticosteroids after intraocular administration, given the ultra-low plasma concentrations achieved. In summary, this strategy enables PK analysis of corticosteroids in treatment regimens that result in extremely low systemic concentrations, and the approach can be extended for the sensitive quantification of other drugs.
机译：低剂量皮质类固醇可以为许多治疗应用提供有利的益处/风险比。然而，实现了极低的血浆药物浓度，结合目前分析方法的不充分敏感性/选择性，使皮质类固醇药代动力学（PK）在这种条件下的重大挑战的评估。此外，涉及吸入或眼内注射施用的靶向治疗策略可能导致非常低但持续的全身皮质类固醇浓度，必须定量测量以确定潜在的副作用。在这里，我们描述了一种稳健的方法，用于血浆样品中皮质类固醇的超敏定量。这是通过选择性固相萃取（SPE）与高敏感毛细管LC（（MU）LC）-MS / MS分析的组合来实现的。优化SPE洗涤和洗脱条件，以便从血浆中选择性地提取靶药物。通过从样品基质中消除最不期望的化合物，该选择性SPE过程使（MU）LC柱上的高样品负载量，而不会损害色谱性能和操作稳健性，并有助于实现血浆中皮质类固醇的超低检测限。研究了（MU）LC分离对等离子体样品中皮质类固醇峰的信噪比的影响。发现具有足够的（mU）LC分离，由于基质效应和去除内源干扰，因此改善了灵敏度。四种临床 - 重要的皮质类固醇（预烯醇，地塞米松，抗菊肉酮酮酮酮酮酮酮和乙酸酯）的检测限范围为0.2-1pg / ml，在血浆中为0.2-1pg / ml，对于所有药物的线性有益于5-5,000pg / ml。准确性为88-107％，变异（CV（百分比））为2.3-11。为所有4种化合物验证了5pg / ml的定量限制（LOQ）。我们应用该方法以量化猪血浆给药后猪血浆中的曲胺酮（TACA）的低水平，这是估计这种新临床方法治疗眼睛炎症疾病所产生的全身药物暴露。血浆中的炸菌饼可以在低pg / ml水平下量化，在治疗后长达90天。鉴于我们的知识，这是鉴于实现的超低等离子体浓度，可以在眼内给药后监测血浆皮质类固醇的第一种实用分析方法。总之，该策略使得PK分析皮质类固醇在治疗方案中产生极低的系统性浓度，并且可以延长其他药物的敏感量化的方法。

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