title: Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination.
abstract: Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5'-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.
authors.affiliation: Oncology Innovative Medicines DMPK, AstraZeneca, Alderley Park, Cheshire, UK. christopher.jones@heptares.com.|Heptares Therapeutics Ltd, BioPark Broadwater Road, Welwyn Garden City, AL73AX, UK. christopher.jones@heptares.com.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Oliver J D
authors.initials: OJ
authors.lastname: Hatley
authors.affiliation: CVMD Innovative Medicines DMPK, AstraZeneca, Mölndal, Sweden.|Investigative ADME, Non Clinical Development, UCB New Medicines, BioPharma SPRL, Chemin de Foriest, B-1420, Braine A'lleud, Belgium.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ungell
authors.affiliation: Drug Safety and Metabolism DMPK, AstraZeneca, Mölndal, Sweden.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.affiliation: Modelling and Simulation, Respiratory, Inflammation and Autoimmunity Innovative Medicines DMPK, AstraZeneca, Mölndal, Sweden.
authors.forename: Sheila Annie
authors.initials: SA
authors.lastname: Peters
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester School of Pharmacy, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000818:Animals; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005544:Forecasting; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System
keywords: animal models; drug-metabolising enzymes; first-pass oral clearance; gut wall metabolism; oral bioavailability