Ion-suppression effects in liquid chromatography-tandem mass spectrometry due to a formulation agent, a case study in drug discovery bioanalysis
Ion-suppression effects in liquid chromatography-tandem mass spectrometry due to a formulation agent, a case study in drug discovery bioanalysis
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DOI：
10.1016/j.jpba.2005.03.009
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发表时间：
2005-09-01
影响因子：
3.4
通讯作者：
James, CA
中科院分区：
文献类型：
--
作者：
Larger, PJ;Breda, M;James, CA
液相色谱-串联质谱（LC/MS/MS）由于其高选择性和高样品通量已成为生物分析的首选技术。然而，人们越来越担心这种技术可能会受到“看不见的”干扰的影响，特别是离子抑制。对制剂中离子抑制作用的研究仅在有限范围内发表。这种效应在临床前发现研究中可能特别重要，因为药物可能含有大量的增溶剂，生物分析可能使用快速的仿制方法。在初步的药代动力学研究中，我们观察到来自聚山梨酯共溶剂的强离子抑制，如果未被检测到，将会给出高度错误的药代动力学结果，并可能导致不适当地消除有希望的候选药物。对不同的色谱方法进行了测试，表明分离步骤是控制这些影响的关键。提出了一种基于矩阵稀释的方法来检查在使用发现支持方法期间的这些影响，其中完全验证是不实际的。配方中常用的一些赋形剂是多分散聚合物，其药代动力学信息非常有限。为了更好地了解离子抑制的机制和抑制物种的动力学，需要进一步的研究，以便开发新的基于LC/MS/MS的分析策略，这些策略将不会受到这种电离干扰。(c) 2005 Elsevier B.V.版权所有
Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has become the technology of choice for bioanalysis, due to its high selectivity and high sample throughput. However, concerns have grown that this technique may be subject to errors due to "invisible" interferences, in particular ion-suppression. Investigations on ion-suppression from formulation agents have only been published to a limited extent. Such effects can be of particular importance in pre-clinical discovery studies where drugs may be formulated with large amount of solubilisers and bioanalysis may use fast generic methods. In a preliminary pharmacokinetic study we observed strong ion-suppression from a polysorbate co-solvent, which, if undetected, would have given highly erroneous pharmacokinetic results and possibly could have led to the inappropriate elimination of a promising drug candidate. Different chromatographic methods were tested indicating that the separation step was essential in controlling these effects. A method based on matrix dilution is proposed to check for these effects during the use of discovery support methods, where full validation is not practical. Some excipients commonly used in formulations are polydispersed polymers, for which very limited pharmacokinetic information is available. Further investigation is needed to better understand the mechanisms of ion-suppression and the kinetics of the suppressing species to allow the development of new LC/MS/MS based analytical strategies, which will not be subject to such ionisation interferences. (c) 2005 Elsevier B.V. All rights reserved.