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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2016

Open Access 01-06-2016 | Review Article

Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models

Authors: Sheila Annie Peters, Christopher R. Jones, Anna-Lena Ungell, Oliver J. D. Hatley

Published in: Clinical Pharmacokinetics | Issue 6/2016

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Abstract

Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models—in vivo, in situ and in vitro—have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.
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Metadata
Title
Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models
Authors
Sheila Annie Peters
Christopher R. Jones
Anna-Lena Ungell
Oliver J. D. Hatley
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0351-6

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