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

Synthesis of ¹³C-Lidocaine as a Probe of Breath Test for the Evaluation of Cytochrome P450 Activity

“…5,6) In general, the assessment of in vivo CYP activity is performed by administration of a selective probe for the target enzyme and the subsequent determination of the appropriate pharmacokinetic parameters, or by using the metabolism of endogenous substrates. 7,8) Above all, breath tests, where a 13 C-or 14 C-labeled drug is administered as a probe followed by measurement of the labeled CO 2 in expiration, are advantageous in that the procedures are simple and convenient, particularly in clinical settings. Although such breath tests have been studied for various CYP isoforms, 9) a breath test for CYP3A4 is of great value because the isoform is the most abundant and versatile.…”

“…However, this method has a safety problem for clinical application due to its radioactivity. Thus, the method to use 13 C-EM instead of 14 C-EM as a probe was developed, where the exhaled 13 CO 2 in breath is measured with an infrared (IR) spectrometer.…”

“…13) The CYP3A inhibition and induction were quantitatively evaluated by this breath test, in which 13 C-EM was intravenously administrated to rats. However, the method requires a high dose because of the large molecular weight of 13 C-EM.…”

“…However, the method requires a high dose because of the large molecular weight of 13 C-EM. In addition, 13 C-EM is not suitable for oral administration because the drug is susceptible to decomposition by gastric acid, which may hinder the quantitative evaluation of CYP activity. Recently, attention has been paid to the small intestine as an extrahepatic drug-metabolizing organ.…”

“…CYP3A4 has been reported to be a predominant CYP isoform in human small intestine. 14,15) Thus, another 13 C-labeled probes are desired for a breath test to evaluate CYP3A4 activity by oral administration .…”