The Use of 13C–Erythromycin as an in vivo Probe to Evaluate CYP3A-mediated Drug Interactions in Rats

14C–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 13C (13C–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 13CO2 exhalation altered by drug interactions was newly constructed. Rats received an intravenous or oral administration of 13C–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 Δ13CO2 value (‰) in each sample was obtained. The Cmax and AUC0–t of Δ13CO2 were significantly decreased with KCZ and increased with DEX. The PBPK model in this study successfully described the 13CO2 exhalation after 13C–EM administration in the absence and presence of drug interactions. In conclusion, this study proposed a simple and rapid in vivo methodology to utilize 13C–EM for the quantitative analysis of CYP3A inhibition and induction. This method using small animals may be useful in early drug development processes. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3995–4005, 2011