Bergamottin can be used to assess CYP3A-mediated intestinal first-pass metabolism without affecting P-glycoprotein-mediated efflux in rats

Abstract

1. We investigated whether bergamottin would be useful for evaluating CYP3A-mediated intestinal metabolism in rats utilising its characteristics as a mechanism-based inhibitor of CYP3A.

2. Buspirone and fexofenadine, probe substrates of CYP3A and P-glycoprotein (P-gp), respectively, were orally co-administered to rats with bergamottin (2.5 mg/kg) or orally administered 2 h after bergamottin pre-treatment. The effect of bergamottin pre-treatment on hepatic CYP3A specifically was investigated with intravenous administration of buspirone. The k_obs of bergamottin for CYP3A was calculated based on the portal unbound C_max.

3. Co-administration of bergamottin significantly increased the AUC_0–inf for buspirone and fexofenadine by 1.6-fold and 1.7-fold, respectively, indicating that bergamottin inhibited both CYP3A and P-gp.

4. Bergamottin pre-treatment significantly elevated the AUC_0–inf of oral buspirone by 3.7-fold but exerted no effect on the pharmacokinetics of intravenous buspirone, indicating that bergamottin pre-treatment selectively inhibited CYP3A-mediated intestinal metabolism without affecting the hepatic CYP3A. These findings were supported by the result that the k_obs (0.00000118 min⁻¹) of bergamottin for CYP3A was lower than the k_deg (0.0005 min⁻¹) for CYP3A. Furthermore, bergamottin pre-treatment did not affect the pharmacokinetics of oral fexofenadine, suggesting that P-gp was not influenced.

5. These profiles of bergamottin enable the convenient assessment of CYP3A-mediated intestinal metabolism.

Keywords:

• Bergamottin
• CYP3A
• P-gp
• rats
• intestinal metabolism

Acknowledgements

The authors thank Takashi Sato (TOA EIYO Ltd.) for valuable discussions. The authors would like to thank Enago (www.enago.jp) for the English language review.

Disclosure statement

The authors report no conflict of interest.