New model identifies drugs that should not be taken together

Any medication taken orally must pass through the lining of the digestive tract. Transport proteins on the cells lining the digestive tract help with this process, but for many drugs it is not known which of these transporters they use to exit the digestive tract.

Identifying the transporters used by specific drugs could help improve patient treatment, because if two drugs depend on the same transporter, they may interfere with each other and should not be prescribed together.

Researchers from MIT, Brigham and Women’s Hospital and Duke University have developed a multi-pronged strategy to identify transporters used by different drugs. Their approach, which uses 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 of modeling absorption is that drugs are subject to different transporters. This study focuses on how we can model these interactions, which could help us make drugs safer and more effective , and to predict potential toxicities that might have been difficult to assess.” predict so far,” says Giovanni Traverso, associate professor of mechanical engineering at MIT, gastroenterologist at Brigham and Women’s Hospital and senior author of the study.

Learning more about the transporters that help drugs pass through the digestive tract could also help drug developers improve the absorption capacity of new drugs by adding excipients that improve their interactions with transporters.

Former MIT postdocs Yunhua Shi and Daniel Reker are lead authors of the study, published today in Natural biomedical engineering.

Drug transportation

Previous studies have identified several transporters in the gastrointestinal tract that help drugs cross the intestinal lining. Three of the most commonly used ones, which were the subject of the new study, are BCRP, MRP2 and PgP.

For this study, Traverso and colleagues adapted a tissue model they developed in 2020 to measure the absorption capacity of a given drug. This experimental setup, based on laboratory-grown pig intestinal tissues, can be used to systematically expose tissues to different drug formulations and measure their absorption.

To study the role of individual transporters in tissue, researchers used short strands of RNA called siRNA to inhibit the expression of each transporter. In each section of tissue, they destroyed different combinations of transporters, which allowed them to study how each transporter interacts with many different drugs.

“There are a few routes that drugs can take through tissue, but you don’t know which route. We can close the roads separately to determine if we close this road, are the drugs still coming through there? If the answer is yes, then he doesn’t use that route,” says Traverso.

The researchers tested 23 commonly used drugs using this system, allowing them to identify the transporters used by each of these drugs. Then, they trained a machine learning model on this data, as well as data from several drug databases. The model learned to predict which drugs would interact with which transporters, based on similarities between the chemical structures of the drugs.

Using this model, the researchers analyzed a new set of 28 currently used drugs, as well as 1,595 investigational drugs. This review yielded nearly 2 million predictions of potential drug interactions. Among them was the prediction that the antibiotic doxycycline might interact with warfarin, a commonly prescribed blood thinner. Doxycycline was also expected to interact with digoxin, used to treat heart failure, levetiracetam, an antiepileptic drug, and tacrolimus, an immunosuppressant.

Identify interactions

To test these predictions, researchers looked at data from about 50 patients who were taking one of these three drugs when they were prescribed doxycycline. These data, from a patient database at Massachusetts General Hospital and Brigham and Women’s Hospital, showed that when doxycycline was given to patients already taking warfarin, the level of warfarin in the patients’ blood increased. , then went back down after their capture. I stopped taking doxycycline.

These data also supported model predictions that doxycycline absorption is affected by digoxin, levetiracetam, and tacrolimus. Only one of these drugs, tacrolimus, had been suspected of interacting with doxycycline.

“These are commonly used drugs, and we are the first to predict this interaction using this accelerated in silico and in vitro model,” says Traverso. “This type of approach gives you the opportunity to understand the potential safety implications of administering these drugs together.”

In addition to identifying potential interactions between drugs already in use, this approach could also be applied to drugs currently in development. Using this technology, drug developers could adjust the formulation of new drug molecules to prevent interactions with other drugs or improve their absorbability. Vivtex, a biotechnology company co-founded in 2018 by former MIT postdoc Thomas von Erlach, MIT Professor Robert Langer and Traverso to develop new oral drug delivery systems, is now pursuing this type of drug tuning .

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and education.