The use of 13C-erythromycin as an in vivo probe to evaluate CYP3A-mediated drug interactions in rats

J Pharm Sci. 2011 Sep;100(9):3995-4005. doi: 10.1002/jps.22616. Epub 2011 May 26.


(14)C-erythromycin breath test has been utilized to evaluate the extent of CYP3A activity in vivo. However, its radioactivity sometimes impedes its clinical application. In this study, we employed erythromycin labeled with (13)C ((13)C-EM), a nonradioactive stable isotope, as an in vivo probe of breath test to evaluate CYP3A-mediated drug interactions in rats. A physiologically based pharmacokinetic (PBPK) model to describe (13)CO(2) exhalation altered by drug interactions was newly constructed. Rats received an intravenous or oral administration of (13)C-EM with or without a CYP3A inhibitor or inducer, that is, ketoconazole (KCZ) or dexamethasone (DEX), respectively. Breath samples were taken at designated times, measured with an infrared spectrophotometer, and the Δ(13) CO(2) value (‰) in each sample was obtained. The C(max) and AUC(0-t) of Δ(13) CO(2) were significantly decreased with KCZ and increased with DEX. The PBPK model in this study successfully described the (13)CO(2) exhalation after (13)C-EM administration in the absence and presence of drug interactions. In conclusion, this study proposed a simple and rapid in vivo methodology to utilize (13)C-EM for the quantitative analysis of CYP3A inhibition and induction. This method using small animals may be useful in early drug development processes.

MeSH terms

  • Animals
  • Breath Tests
  • Carbon Dioxide / analysis
  • Carbon Isotopes
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Interactions
  • Erythromycin / blood
  • Erythromycin / pharmacokinetics*
  • Molecular Probes
  • Rats
  • Spectrophotometry, Infrared


  • Carbon Isotopes
  • Molecular Probes
  • Carbon Dioxide
  • Erythromycin
  • Cytochrome P-450 CYP3A