Using engineered mini-livers derived from donated human cells, MIT researchers have found that the time of day a drug is administered could significantly affect how much of it is available to the body and how much may be broken down into toxic by-products.
The researchers identified more than 300 liver genes that follow a circadian clock, including many involved in drug metabolism and others that are involved in inflammation. Because of these rhythmic variations in gene activity, enzymes that break down Tylenol, for example, are more abundant at certain times of day than others.
The study also revealed that the liver is more susceptible to infections such as malaria at certain points in the circadian cycle, when fewer inflammatory proteins are being produced—possibly because its response to pathogens declines after meals, when it has typically been exposed to an influx of microorganisms that might trigger inflammation even if they are not harmful.
“One of the earliest applications for this method could be fine-tuning drug regimens of already approved drugs to maximize their efficacy and minimize their toxicity,” says Professor Sangeeta Bhatia, SM ’93, PhD ’97, a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science (IMES), who is the senior author of the new study.
The MIT researchers are now working with collaborators to analyze a cancer drug they suspect may be affected by circadian cycles, and they hope to investigate whether this may be true of drugs used in pain management as well. They are also taking advantage of the cycles in inflammatory signals to study infections that are usually difficult to establish in engineered livers, including certain types of malaria.
