Researchers from MIT, Brigham and Women’s Hospital, and Duke University have developed a strategy to understand how orally ingested drugs exit the digestive tract. The process relies on transporter proteins found in the lining of the digestive tract. Identifying the specific transporters used by various drugs can help avoid potential complications when two drugs using the same transporter are prescribed together. The research team used a combination of tissue models and machine learning algorithms to understand these interactions.
The researchers noted that understanding how various transporters aid drugs through the digestive system could help enhance the efficacy of new drugs by adding excipients which improve their interactions with transporters. The research, led by MIT’s Associate Professor of Mechanical Engineering and senior author of the study, Giovanni Traverso, focused on three commonly used transporters – BCRP, MRP2, and PgP.
The team employed a lab-grown pig intestinal tissue model developed in 2020 to evaluate drug absorbability. To study the role of individual transporters, they used short strands of RNA called siRNA to reduce the expression of each transporter, enabling the study of how each transporter interacts with various drugs.
This system allowed the testing of 23 commnonly used drugs and identification of transporters used by each one. Using this data and additional data from drug databases, they trained a machine-learning model to predict which drugs would interact with which transporters, based on drug chemical structures.
The model was used to analyse a new set of 28 currently used drugs, as well as 1,595 experimental drugs, and yielded nearly 2 million predictions of potential drug interactions. For instance, the antibiotic doxycycline was predicted to interact with the blood thinner warfarin, as well as heart failure drug digoxin, antiseizure medication levetiracetam, and immunosuppressant tacrolimus.
The researchers confirmed predictions by looking at data from about 50 patients who had been prescribed one of those three drugs along with doxycycline. The results showed a temporary increase in warfarin concentration in the bloodstream after adding doxycycline, which normalized after discontinuing the antibiotic.
The researchers also confirmed the model’s predictions that absorption of doxycylline was affected by digoxin, levetiracetam and tacrolimus. Only one, tacrolimus, had been previously suspected to interact with doxycycline.
The approach could prove beneficial to drug developers by allowing them to tweak the formulation of new medications to avoid adverse drug interactions and improve absorbability. Vivtex, a biotech company focusing on the development of new oral drug delivery systems, is currently pursuing such applications.
The study was funded by the U.S. National Institutes of Health, the Department of Mechanical Engineering at MIT, and the Division of Gastroenterology at Brigham and Women’s Hospital. The results of the study have been published in Nature Biomedical Engineering.
