Radiolabelled mass-balance excretion and metabolism studies in laboratory animals: are they still necessary?

Xenobiotica. 2012 Jan;42(1):46-56. doi: 10.3109/00498254.2011.621985. Epub 2011 Oct 12.


The conduct of excretion and metabolism studies using radiolabelled drugs in multiple laboratory animal species has been a mainstay of the suite of support activities provided by drug metabolism groups within pharmaceutical research and development organizations for decades. Drug metabolism scientists carry out exhaustive analyses of plasma and excretory matrices to comprehensively determine the profiles of metabolites in these species. While these analyses have taught us considerably regarding principles of drug metabolism and excretion, it is our contention that the routine conduct of such studies for every new drug development compound in every laboratory animal species used in toxicology studies is no longer necessary. The recently released regulatory guidance regarding metabolites and safety testing have better defined what we need to know regarding metabolite profiles in humans relative to animals. In this commentary, we propose a strategy wherein a radiolabel metabolism study is conducted only in humans, and that these data are utilized as a springboard to direct the exploration of steady-state human versus animal metabolite exposures. Such a strategy better serves the purpose of what is needed to support our understanding of the safety of a new drug candidate. Valuable expertise in drug metabolism and biotransformation can be redeployed to meet the burgeoning needs in drug design efforts to optimize structures with regard to metabolic clearance properties, understanding pharmacologically active metabolites, and reducing generation of chemically reactive metabolites.

Publication types

  • Review

MeSH terms

  • Animal Testing Alternatives
  • Animals
  • Animals, Laboratory
  • Biotransformation
  • Carbon Radioisotopes
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Isotope Labeling
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics


  • Carbon Radioisotopes
  • Pharmaceutical Preparations