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

Bioanalysis. 2017 Dec;9(23):1913-1933. doi: 10.4155/bio-2017-0137. Epub 2017 Nov 24.


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.

Keywords: LC–MS/MS; SPECT; accelerator mass spectrometry; drug metabolism; drug target; metabolomics; microdosing; pharmacokinetics; positron emission tomography; radioisotope; radiotracer; single-photon emission computed tomography.

Publication types

  • Review

MeSH terms

  • Drug Discovery
  • Isotope Labeling*
  • Metabolomics*
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Positron-Emission Tomography
  • Radiation Dosage
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism*
  • Tomography, Emission-Computed, Single-Photon


  • Pharmaceutical Preparations
  • Radiopharmaceuticals