The number of samples to be analyzed during the drug discovery process is constantly increasing. Therefore, fast, selective and sensitive analytical methods are required. Nowadays, liquid chromatography coupled with mass spectrometry (LC-MS) is considered as the method of choice. With this performant tool, the sample preparation step prior to analysis can be simplified and the analytical process speeded up. Therefore, several sample extraction techniques, coupled on-line with a LC-MS system, have recently been developed. In this work, different extraction supports allowing the direct injection of biological fluids were investigated. In the single column mode or in the column switching configuration, these supports were found suitable for the fast analysis (less than 15 min) of drugs and their metabolites present at ng.ml-1 level in biological matrices.