<p>This work details how to obtain quantitative results in drug metabolism studies through fluorine detection, utilizing an optimized capillary liquid chromatography setup coupled with inductively coupled plasma tandem mass spectrometry (LC-ICP-MS/MS). This approach eliminates the need for authentic standards or specific labeling with radioactive tritium or carbon-14, enabling targeted and quantitative metabolite identification in much earlier stages of drug discovery and development. Eluent composition was optimized towards selectivity and sensitivity, with correction for gradient effects achieved through both counter gradient application and model-based data correction. The setup allows a limit of detection below 1 ng of fluorine injected on the&#xa0;column for a chromatographic peak&#xa0;to be achieved. High mass spectrometry sensitivity, combined with the ability to inject volumes up to 400 µL via a trap-elute injection, enables selective and sensitive detection of fluorinated drugs and their metabolites at relevant levels for in vitro and in vivo samples in various matrices. The workflow was validated via direct comparison with radioactivity detection, making use of ¹⁴C-radiolabeled drugs. This approach holds significant potential to shape future study designs in absorption, distribution, metabolism, and excretion studies.</p> Graphical abstract <p></p>