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

摘要

This review discusses the use of stable (C-13, D-2) or radioactive isotopes (C-14, C-11, F-18, I-131, Cu-64, Ga-68) 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-humanmetabolite studies have to be carried out at nonpharmacological doses not exceeding 100 mu g (microdose), which is generally too low for metabolite detection by LC-MS/MS. This short-coming can be overcome by specific radioor isotopic labeling of the drug of interest and measurements using accelerator mass spectroscopy, singlephoton emission computed tomography and positron emission tomography. Such combined radioisotopebased approaches permit Phase 0, first-in-human metabolite study.