Potential role of intestinal first-pass metabolism in the prediction of drug–drug interactions

Abstract

Background: The contribution of intestine to the magnitude of drug–drug interactions (DDI) may be significant, considering high levels of inhibitors in the gut lumen achieved during absorption and the abundance of metabolic enzymes in the mature enterocytes. Intestinal inhibition is incorporated in the DDI prediction models as the ratio of the intestinal wall availability in the presence and absence of the inhibitor (F_G^′ and F_G, respectively). Objective: This review will focus on the ability of the current approaches to estimate the extent of intestinal DDI accurately, addressing predominantly the most abundant intestinal P450 enzyme, CYP3A4. Methods: Considering the sensitivity of the DDI prediction models to the accuracy of the F_G estimates, the current study focuses on 3 different in vitro and in vivo approaches to assess this parameter. Results/conclusion: The advantages and limitations of each of F_G methods are outlined. Accurate assessment of this parameter is essential for the prediction of human drug clearance and drug–drug interaction potential.

Keywords::

• CYP3A4
• drug–drug interactions
• intestinal first-pass

Declaration of interests

The Authors have no conflict of interests.

The work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester.

Financial support for AG academic position in the School of Pharmacy and Pharmaceutical Sciences, University of Manchester and MG PhD studentship was kindly provided by Pfizer, Sandwich, UK.

Acknowledgements

The Authors would like to thank Eleanor Guest (University of Manchester) for her assistance with collation of i.v./oral clinical data.

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