That’s according to new research looking to identify transporter proteins used by oral drugs to pass through the lining of the digestive tract.
Researchers at MIT, Brigham and Women’s Hospital, and Duke University suggest that identifying the transporters used by specific drugs could help improve patient care. They caution that if two drugs rely on the same transporter, they can interfere with each other and should not be prescribed together.
The new approach described in Nature Biomedical Engineering uses both tissue models and machine-learning algorithms.
“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,” explained senior author Giovanni Traverso, MD, PhD, MBBCH, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital.
“In vitro systems that accurately model in vivo conditions in the gastrointestinal tract may aid the development of oral drugs with greater bioavailability,” the authors wrote. “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.”
The authors noted that the model achieved 100% concordance. For 28 clinical drugs and 22 investigational drugs for 24 drugs with well-characterized drug-transporter interactions, while also identifying 58 unknown drug-transporter interactions. Of those, seven out of eight 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,” the authors wrote. “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.”
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.
The tissue model was developed in 2020 to measure a given drug’s absorbability. The current experimental setup is based on pig intestinal tissue grown in the laboratory and can be used to systematically expose tissue to different drug formulations to measure how well they are absorbed.
Short strands of RNA (siRNA) were used to study the role of individual transporters within the tissue. The goal was determining 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,” Dr. Traverso advised.
Using the model, the study team analyzed a new set of 28 currently used drugs, as well as 1,595 experimental drugs. That yielded nearly 2 million predictions of potential drug interactions, including those involving doxycycline.
Those findings were compared to data from about 50 patients who had been taking one of the three drugs in question when they were prescribed doxycycline. The data from Massachusetts General Hospital and Brigham and Women’s Hospital indicated that when doxycycline was given to patients already taking warfarin, the level of warfarin in the patients’ bloodstream went up, then went back down again after they stopped taking doxycycline.
That data also confirmed the model’s predictions that the absorption of doxycycline is affected by digoxin, levetiracetam, and tacrolimus. Only one of those drugs, tacrolimus, had been previously suspected to interact with doxycycline.
“These are drugs that are commonly used, and we are the first to predict this interaction using this accelerated in silico and in vitro model,” Dr. Traverso said. “This kind of approach gives you the ability to understand the potential safety implications of giving these drugs together.”
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