An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: the role of PBPK modeling

ABSTRACT

Introduction: The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug–drug interactions (DDIs).

Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs. It also provides a comprehensive overview and summary of the latest update in the role of physiologically based pharmacokinetic models modeling in prediction of intestinal metabolism and DDIs in humans.

Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.

KEYWORDS:

• Intestinal first-pass metabolism
• drug–drug interactions
• PBPK
• bioavailability

Article highlights

• Oral administration of drugs is considered the most convenient route for drug administration as it leads to better therapy compliance. Drugs must have specified physicochemical properties to be successful candidates for oral administration.

• Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs.

• There is a notable overlap between P-gp and CYP3A substrates and tissue expression, and both influence the F of orally administered drugs.

• Several clinical studies have provided a clear evidence for the substantial role of intestinal first-pass metabolism in oral F and potential DDIs.

PBPK models provide an effective and reliable tool to evaluate the role of intestinal first-pass metabolism in the prediction of potential DDIs.

Acknowledgments

The author was supported by the College of Pharmacy Research Center and the Deanship of Scientific Research, King Saud University (Riyadh, Saudi Arabia).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The author was supported by the College of Pharmacy Research Center and the Deanship of Scientific Research, King Saud University (Riyadh, Saudi Arabia).