In vivo evaluation of intestinal human CYP3A inhibition by macrolide antibiotics in CYP3A-humanised mice

Abstract

1. It is important to predict drug-drug interactions via inhibition of intestinal cytochrome P450 3A (CYP3A) which is a determinant of bioavailability of orally administered CYP3A substrates. However, inhibitory effects of macrolide antibiotics on CYP3A-mediated metabolism are not entirely identical between humans and rodents.

2. We investigated the effects of macrolide antibiotics, clarithromycin and erythromycin, on in vitro and in vivo metabolism of triazolam, a CYP3A substrate, in CYP3A-humanised mice generated by using a mouse artificial chromosome vector carrying a human CYP3A gene.

3. Metabolic activities of triazolam were inhibited by macrolide antibiotics in liver and intestine microsomes of CYP3A-humanised mice.

4. The area under the plasma concentration-time curve ratios of 4-hydroxytriazolam to triazolam after oral dosing of triazolam were significantly decreased by multiple administration of macrolide antibiotics. The plasma concentrations ratios of α-hydroxytriazolam and 4-hydroxytriazolam to triazolam in portal blood were significantly decreased by multiple administration of clarithromycin in CYP3A-humanised mice.

5. These results suggest that intestinal CYP3A activity was inhibited by macrolide antibiotics in CYP3A-humanised mice in vitro and in vivo. The plasma concentrations of triazolam and its metabolites in the portal blood of CYP3A-humanised mice would be useful for direct evaluation of intestinal CYP3A-mediated drug-drug interactions.

Keywords:

• Cytochrome P450 3A
• drug-drug interaction
• humanised mice
• intestinal metabolism
• macrolide antibiotics
• triazolam

Acknowledgments

We thank Yukako Sumida, Toko Kurosaki, Kei Yoshida, Eri Kaneda, Masami Morimura, Michika Fukino and Akiko Ashiba at Tottori University for technical assistance in the experiment. This research was partly performed at the Tottori Bio Frontier managed by Tottori Prefecture.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported in part by the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency for Medical Research and Development (AMED) under grant number JP20am0101124 (YK) and JSPS KAKENHI Grant Number JP19K07159 (KK).