• Application of a bioengineered...

Treffer: Application of a bioengineered intestinal epithelium for drug permeability and metabolism studies.

Title:
Application of a bioengineered intestinal epithelium for drug permeability and metabolism studies.
Authors:
Gill E; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.; Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. nicolo.milani@roche.com., Muenchau Schoepp S; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.; Roche Pharmaceutical Research and Development, Synthetic Molecules Technical Development, Basel, Switzerland., Simon S; Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. nicolo.milani@roche.com., Harter MF; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.; Gustave Roussy Cancer Campus, University Paris-Saclay, Paris, France., Nikolaev M; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com., Pereiro I; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com., Silva I; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com., López-Sandoval R; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.; Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland., Berrera M; Data & Analytics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland., Kam-Thong T; Data & Analytics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland., Michalski M; 360 Labs, Strategy, Portfolio and Operations (SPO), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland., Zaayman M; 360 Labs, Strategy, Portfolio and Operations (SPO), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland., Aubert J; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com., Cubela I; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com., Keemink J; Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. nicolo.milani@roche.com., Stillhart C; Roche Pharmaceutical Research and Development, Synthetic Molecules Technical Development, Basel, Switzerland., Hofmann M; Roche Pharmaceutical Research and Development, Synthetic Molecules Technical Development, Basel, Switzerland., Fowler S; Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. nicolo.milani@roche.com., Camp JG; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.; Biozentrum, University of Basel, Basel, Switzerland., Milani N; Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. nicolo.milani@roche.com., Gjorevski N; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. nikolche.gjorevski@roche.com.
Source:
Lab on a chip [Lab Chip] 2025 Dec 02; Vol. 25 (24), pp. 6533-6549. Date of Electronic Publication: 2025 Dec 02.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101128948 Publication Model: Electronic Cited Medium: Internet ISSN: 1473-0189 (Electronic) Linking ISSN: 14730189 NLM ISO Abbreviation: Lab Chip Subsets: MEDLINE
Imprint Name(s):
Original Publication: Cambridge, UK : Royal Society of Chemistry, c2001-
MeSH Terms:
Intestinal Mucosa*/metabolism , Bioengineering*, Humans ; Permeability ; Pharmaceutical Preparations/metabolism ; Organoids/metabolism
Substance Nomenclature:
0 (Pharmaceutical Preparations)
Entry Date(s):
Date Created: 20251117 Date Completed: 20251205 Latest Revision: 20251205
Update Code:
20251205
DOI:
10.1039/d5lc00626k
PMID:
41247036
Database:
MEDLINE

Weitere Informationen

The small intestine is the most important site of absorption for many orally administered drugs. Following absorption, intestinal and hepatic first-pass metabolism reduce the amount of drug that reaches the systemic circulation and hence the intended therapeutic target. In vitro models can be used to predict intestinal permeability and metabolism, enabling optimization of drug candidate properties for improved oral bioavailability. Currently, data from separate metabolism and permeability assays is combined using modelling approaches, but this does not allow for assessment of interconnected processes. An in vitro system which captures both intestinal permeability and metabolism could improve human pharmacokinetics (PK) prediction accuracy. In this study, a human organoid based bioengineered intestinal epithelium (BIE) with apical and basolateral partitioning and crypt-axis patterning was characterized with regards to barrier function as well as the presence of key drug-metabolizing enzymes (DMEs) and drug transporters (DTs). Drug transport studies validated the function of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) through targeted inhibition. Furthermore, the BIE's capability to estimate drug metabolic parameters is demonstrated through mathematical mechanistic modeling to predict the fraction escaping gut metabolism ( F<subscript>g</subscript> ). Results indicate consistent tissue patterning and the potential to assess drug permeability and metabolism in the gut simultaneously. The use of intestinal organoids in a microphysiological system coupled with in silico modeling holds significant promise to innovate oral drug bioavailability assessment and aid in drug formulation and safety screening.