Microdosing, isotopic labeling, radiotracers and metabolomics: relevance in drug discovery, development and safety. (December 2017)

• Record Type: Journal Article
• Authors: Wotherspoon, Andrew TL; Safavi-Naeini, Mitra; Banati, Richard B
• Is Part Of: Bioanalysis. Volume 9:Number 23(2017)
• Page Start: 1913
• Page End: 1933
• Publication Date: 2017-12
• Subjects: accelerator mass spectrometry -- drug metabolism -- drug target -- LC–MS/MS -- metabolomics -- microdosing -- pharmacokinetics -- positron emission tomography -- radioisotope -- radiotracer -- single-photon emission computed tomography -- SPECT; Drugs -- Analysis -- Periodicals; 615.19005
• DOI: 10.4155/bio-2017-0137
• Languages: English
• ISSNs: 1757-6180

Abstract

This review discusses the use of stable ( 13 C, 2 D) or radioactive isotopes ( 14 C, 11 C, 18 F, 131 I, 64 Cu, 68 Ga) 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.