Journal article
Screening oral drugs for their interactions with the intestinal transportome via porcine tissue explants and machine learning
Nature biomedical engineering, Vol.8(3), pp.278-290
03/2024
DOI: 10.1038/s41551-023-01128-9
PMID: 38378821
Abstract
In vitro systems that accurately model in vivo conditions in the gastrointestinal tract may aid the development of oral drugs with greater bioavailability. Here we show that the interaction profiles between drugs and intestinal drug transporters can be obtained by modulating transporter expression in intact porcine tissue explants via the ultrasound-mediated delivery of small interfering RNAs and that the interaction profiles can be classified via a random forest model trained on the drug-transporter relationships. For 24 drugs with well-characterized drug-transporter interactions, the model achieved 100% concordance. For 28 clinical drugs and 22 investigational drugs, the model identified 58 unknown drug-transporter interactions, 7 of which (out of 8 tested) corresponded to drug-pharmacokinetic measurements in mice. We also validated the model's predictions for interactions between doxycycline and four drugs (warfarin, tacrolimus, digoxin and levetiracetam) through an ex vivo perfusion assay and the analysis of pharmacologic data from patients. Screening drugs for their interactions with the intestinal transportome via tissue explants and machine learning may help to expedite drug development and the evaluation of drug safety.
Details
- Title: Subtitle
- Screening oral drugs for their interactions with the intestinal transportome via porcine tissue explants and machine learning
- Creators
- Yunhua Shi - Brigham and Women's HospitalDaniel Reker - Duke UniversityJames D Byrne - University of IowaAmeya R Kirtane - Brigham and Women's HospitalKaitlyn Hess - Massachusetts Institute of TechnologyZhuyi Wang - Massachusetts Institute of TechnologyNatsuda Navamajiti - Chulalongkorn UniversityCameron C Young - Brigham and Women's HospitalZachary Fralish - Duke UniversityZilu Zhang - Duke UniversityAaron Lopes - Massachusetts Institute of TechnologyVance Soares - Massachusetts Institute of TechnologyJacob Wainer - Massachusetts Institute of TechnologyThomas von Erlach - Massachusetts Institute of TechnologyLei Miao - Massachusetts Institute of TechnologyRobert Langer - Massachusetts Institute of TechnologyGiovanni Traverso - Massachusetts Institute of Technology
- Resource Type
- Journal article
- Publication Details
- Nature biomedical engineering, Vol.8(3), pp.278-290
- DOI
- 10.1038/s41551-023-01128-9
- PMID
- 38378821
- eISSN
- 2157-846X
- Grant note
- EB000244 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
- Language
- English
- Electronic publication date
- 02/20/2024
- Date published
- 03/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiation Oncology
- Record Identifier
- 9984560464002771
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