Metabolic interactions between prokinetic agents domperidone and erythromycin: an in vitro analysis

Abstract

1. This study examined in vitro interaction between domperidone and erythromycin. Both are prescribed for refractory gastroparesis. Domperidone is metabolized via human cytochrome P4503A4. Erythromycin is a CYP3A4 inhibitor.

2. Incubations evaluated domperidone metabolite formation in human liver microsomes and recombinant CYP3A4. Concentration- and time-dependent inhibition of 500 μM domperidone was studied with 2.5–200 μM erythromycin over 10–40 min.

3. Domperidone metabolite (5-hydroxy domperidone, M3) formation was inhibited by erythromycin in a concentration- and time-dependent manner. The K_I estimate was 18.4 μM in human liver microsomes and 4.1 μM in CYP3A4. Using a model incorporating CYP3A4 hepatic and gut inhibition, in vitro estimates from human liver microsomes and CYP3A4 were used to predict in vivo AUC_i/AUC ratios of 2.54 and 4.95, respectively.

4. Significant inhibition of domperidone metabolism by erythromycin occurs. This predicts greater domperidone drug exposure when used with erythromycin. This important drug–drug interaction will be evaluated in future human studies.

Keywords::

• Gastroparesis
• domperidone
• erythromycin
• CYP3A4
• mechanism-based inhibition

Acknowledgements

This work was partially funded by a seed grant to support Temple University faculty research collaborations (H. P. P. and S. N.). This work was accepted for presentation as a poster at the Digestive Disease Week meeting, Chicago, IL, USA, May 2009.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.