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

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.

Expression of clinically relevant drug‐metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra‐subject analysis

“…Phase I and II metabolisms are the undisputed major biotransformation pathways for most drugs on the market; that is, about 75% of marketed drugs are subjected to oxidative modification by CYP3A4, CYP2C8/9/19 and CYP2D6, while about 2/3 of the drugs were described to undergo conjugation reactions with hydrophilic moieties by transferases such as UGTs or SULTs …”

“…The bioavailability of orally administered drugs is influenced by several complex factors, such as gastrointestinal transit, disintegration of dosage forms, drug dissolution, passive as well as active uptake processes, metabolism and efflux transport back to the gut lumen . In the past, the liver was assumed to be the major organ for first‐pass drug metabolism .…”

“…However, there is convincing evidence from several studies that intestinal drug‐metabolizing enzymes can contribute equally or even higher to the first‐pass metabolism of drugs than the liver . Thus, intestinal metabolism can be assumed to be the major reason for the low oral bioavailability of many compounds such as midazolam, nifedipine and some statins …”

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

“…In addition, the under-expression of transporters such as peptide transporter 1 (PEPT1), organic cation transporters (OCTs), and organic anion transporters (OATs), makes the model less suitable for compounds that use these transporters (Larregieu and Benet, 2013). Under-expression of metabolic enzymes (e.g., CYP3A4) and different sulfotransferase and uridine diphospho-glucuronosyltransferase (UGT) enzymes, as compared to the human small intestine, also makes Caco-2 cells a poor model for studying intestinal metabolism (Gregory et al, 2004;Meinl et al, 2008;Peters et al, 2016;Schmiedlin-Ren et al, 1997). Additional limitations of Caco-2 absorption experiments include the smaller tight junctions and a 10-fold thicker unstirred water layer compared with the in vivo situation (Hubatsch et al, 2007;Stenberg et al, 2001).…”

PBPK modeling and simulation in drug research and development

“…The same is true for metabolism and disposition in the gut. Due to the complexity of the metabolism, absorption, and transporter activity involved at the different segments of the gastrointestinal tract, and the unique nature of the of individual compound, PBPK modeling for gut absorption ( F g ) has yet to be optimized22, 23. Drug metabolizing enzyme-transporter interplay, PK prediction in organ impairment population, and allometry scaling down to children younger than 2 years of age (ontogeny and maturation), are among the areas that still need more research.…”