Recent developments in plasma sample preparation methods for targeted metabolomics studies with liquid chromatography mass spectrometry

Targeted metabolomics focuses on the quantification of a selected set of metabolites of interest from biological samples. The obtained data is used to better understand the physiological and pathophysiological state of an organism. Plasma samples are commonly analyzed with liquid chromatography coupled to mass spectrometry but require prior sample preparation. In preclinical studies sample volumes are often limited and metabolites of interest are typically present at low concentrations. As a result, there is a growing need for miniaturized sample preparation methods with high extraction efficiency. This review discusses key aspects in sample preparation highlighting the limitations associated with the more conventional methods, such as limited sample clean-up, low selectivity, long extraction times, limited extraction efficiency and the use of hazardous or toxic organic solvents. To address their challenges, novel sample preparation strategies have been developed. Examples that will be discussed are solid phase microextraction, microextraction by packed sorbents, 3D-printed sorbents, molecularly imprinted polymers, magnetic nanoparticles, magnetic ionic liquid-based liquid-liquid microextraction, dispersive liquid-liquid microextraction, nanoconfined liquid phase nanoextraction and supported liquid membrane-electromembrane extraction. A critical evaluation of these sample preparation methods is presented in the context of targeted metabolomics. Furthermore, inspiration is found in untargeted metabolomics and other bioanalytical applications for alternative sample preparation methods that may hold potential for plasma in targeted metabolomics.