New model identifies drugs that shouldn’t be taken together
Using a machine-learning algorithm, researchers can predict interactions that could interfere with a drug’s effectiveness. Any drug that is taken orally must pass through the lining of the digestive tract. Transporter proteins found on cells that line the GI tract help with this process.
Identifying the transporters used by specific drugs could help to improve patient treatment because if two drugs rely on the same transporter, they can interfere with each other and should not be prescribed together.
Researchers at MIT, Brigham and Women’s Hospital, and Duke University have now developed a multipronged strategy to identify the transporters used by different drugs. Their approach, which makes use of both tissue models and machine-learning algorithms, has already revealed that a commonly prescribed antibiotic and a blood thinner can interfere with each other.
“One of the challenges in modeling absorption is that drugs are subject to different transporters. This study is all about how we can model those interactions, which could help us make drugs safer and more efficacious, and predict potential toxicities that may have been difficult to predict until now,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.
Learning more about which transporters help drugs pass through the digestive tract could also help drug developers improve the absorbability of new drugs by adding excipients that enhance their interactions with transporters.
Former MIT postdocs Yunhua Shi and Daniel Reker are the lead authors of the study, which appears today in Nature Biomedical Engineering.
Drug transport
Previous studies have identified several transporters in the GI tract that help drugs pass through the intestinal lining. Three of the most commonly used, which were the focus of the new study, are BCRP, MRP2, and PgP.
For this study, Traverso and his colleagues adapted a tissue model they had developed in 2020 to measure a given drug’s absorbability. This experimental setup, based on pig intestinal tissue grown in the laboratory, can be used to systematically expose tissue to different drug formulations and measure how well they are absorbed.
To study the role of individual transporters within the tissue, the researchers used short strands of RNA called siRNA to knock down the expression of each transporter. In each section of tissue, they knocked down different combinations of transporters, which enabled them to study how each transporter interacts with many different drugs.
“There are a few roads that drugs can take through tissue, but you don't know which road. We can close the roads separately to figure out, if we close this road, does the drug still go through? If the answer is yes, then it’s not using that road,” Traverso says.
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