title: 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.
authors.affiliation: Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Frankfurter Str. 250, F130/005, 64293, Darmstadt, Germany. sheila-annie.peters@merckgroup.com.
authors.forename: Sheila Annie
authors.initials: SA
authors.lastname: Peters
authors.affiliation: Oncology Innovative Medicines DMPK, AstraZeneca, Alderley Park, UK.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: Investigative ADME, Non-Clinical Development, UCB New Medicines, BioPharma SPRL, Braine l'Alleud, Belgium.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ungell
authors.affiliation: Simcyp Limited (A Certara Company), Blades Enterprise Centre, Sheffield, UK.
authors.forename: Oliver J D
authors.initials: OJ
authors.lastname: Hatley
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D020895:Enterocytes / Q000201:enzymology; D018565:Food-Drug Interactions; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D008954:Models, Biological; D010599:Pharmacokinetics; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D015238:Sulfotransferases