Microdosing, isotopic labeling, radiotracers and metabolomics: relevance in drug discovery, development and safety

This review discusses the use of stable (¹³C, ²D) or radioactive isotopes (¹⁴C, ¹¹C, ¹⁸F, ¹³¹I, ⁶⁴Cu, ⁶⁸Ga) incorporated into the molecular structure of new drug entities for the purpose of pharmacokinetic or -dynamic studies. Metabolite in safety testing requires the administration of pharmacologically active doses. In such studies, radiotracers find application mainly in preclinical animal investigations, whereby LC-MS/MS is used to identify metabolite structure and drug-related effects. In contrast, first-in-human metabolite studies have to be carried out at nonpharmacological doses not exceeding 100 μg (microdose), which is generally too low for metabolite detection by LC-MS/MS. This short-coming can be overcome by specific radio- or isotopic labeling of the drug of interest and measurements using accelerator mass spectroscopy, single-photon emission computed tomography and positron emission tomography. Such combined radioisotope-based approaches permit Phase 0, first-in-human metabolite study.