In this study an easy and efficient assay for simultaneous quantitation of plasma concentrations of probe drugs and their metabolically relevant metabolites for the phenotypic analysis of cytochrome P450 2D6 and 2C19, respectively, has been established. This sensitive method makes use of a simple initial sample preparation, followed by a 6-min automated analysis that includes online solid-phase extraction (SPE), column switching and tandem mass spectrometry. Validation over a concentration range of 1.3-2500 ng/mL for dextromethorphan, omeprazole, dextrorphan and 5'-hydroxyomeprazole was performed with LOQ between 215 and 1145 pg/mL. Intra- and inter-day precision and accuracy over the calibration ranges were within 15% for all analytes with recoveries of greater than 85%. Advantages are small sample volumes required, a robust, sensitive and highly selective method suitable for pre-prescription metabolic screening. This method could compliment or offer an alternative to DNA mutation analysis for determining appropriate dosage regimens for personalised medicine.