title: Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development.
abstract: A growing awareness of the risks associated with extensive intestinal metabolism has triggered an interest in developing robust methods for its quantitative assessment. This study explored the utility of intestinal S9 fractions, human liver microsomes, and recombinant cytochromes P450 to quantify CYP3A-mediated intestinal extraction in humans for a selection of marketed drugs that are predominantly metabolized by CYP3A4. A simple competing rates model is used to estimate the fraction of drug escaping gut wall metabolism (fg) from in vitro intrinsic clearance in humans. The fg values extrapolated from the three in vitro systems used in this study, together with literature-derived fg from human intestinal microsomes, were validated against fg extracted from human in vivo pharmacokinetic (PK) profiles using a generic whole-body physiologically-based pharmacokinetic (PBPK) model. The utility of the rat as a model for human CYP3A-mediated intestinal metabolism was also evaluated. Human fg from PBPK compares well with that from the grapefruit juice method, justifying its use for the evaluation of human in vitro systems. Predictive performance of all human in vitro systems was comparable [root mean square error (RMSE) = 0.22-0.27; n = 10]. Rat fg derived from in vivo PK profiles using PBPK has the lowest RMSE (0.19; n = 11) for the prediction of human fg for the selected compounds, most of which have a fraction absorbed close to 1. On the basis of these evaluations, the combined use of fg from human in vitro systems and rats is recommended for the estimation of CYP3A4-mediated intestinal metabolism in lead optimization and preclinical development phases.
authors.affiliation: Cardiovascular and Gastrointestinal Drug Metabolism and Pharmacokinetics (F.H.K., S.B.), Global Drug Metabolism and Pharmacokinetics (C.H., H.D.), and Respiratory, Inflammation and Autoimmunity, Innovative Medicines Drug Metabolism and Pharmacokinetics (S.A.P.), AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Karlsson
authors.forename: Salim
authors.initials: S
authors.lastname: Bouchene
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.forename: Hugues
authors.initials: H
authors.lastname: Dolgos
authors.forename: Sheila Annie
authors.initials: SA
authors.lastname: Peters
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A