Grant to study genetics and drug interaction

Sep 10 2004

A University of Minnesota researcher received a nearly $1 million grant from the National Institutes of Health (NIH) to study how genetic differences affect whether people will experience dangerous drug interactions and how to adjust medications to avoid those interactions.

The NIH awarded the $962,357 grant to College of Pharmacy Professor Timothy S. Tracy, Ph.D., to study how genetic “flaws” affect the body’s response to combinations of medications and what dosing adjustments are necessary.

“People may have dysfunctional enzymes that break down drugs,” Tracy says. “The question we’re asking is, how do these genetic differences affect a person’s susceptibility to drug-to-drug interaction.”

The flaws are found on the enzymes—the parts of the genetic structure to which drug molecules bond—and cause people to react differently when taking certain combinations of medications.

Researchers already know that people’s genetic makeup determines their responses to drugs, a science known as pharmacogenomics. The responses can vary in either how quickly the body metabolizes the drugs or the actual effects the drug has on the person.

Ultimately researchers hope to use a computer model to determine how an individual will respond to drugs and thus reduce potentially serious drug interactions before a drug or combination of drugs is given. It’s what known as individualized drug therapy, a process that allows providers to customize medication dosing for each patient.

“Eventually we’ll have a computer program that says ‘I already know the interactions between Y and Z. Based on that, I can know what the interactions are between X and Z,’” Tracy says.

It’s unclear whether people with the genetic flaws require the same medication dosing adjustments as people without the flaws. And that question is what Tracy will study.

In a drug interaction, competing drug molecules try to bond to the same enzyme. Having competing drug molecules try to attach to the same enzyme is like a game of musical chairs: One of them will get left out, Tracy says. Two drug molecules can compete to sit on the same spot on an enzyme in the body, Tracy says. But if there’s only room for one molecule on that enzyme, the displaced second drug molecule will not be able to bind to the enzyme and thus, not be broken down, he says, creating a potentially serious drug interaction.

To complicate things further, a person’s genetic makeup may alter whether the first drug molecule bonds to an enzyme or whether the molecule is displaced by another drug and left to find a new home. In other words, different genetic structures in an enzyme may increase or decrease the degree to which two drugs compete for the same enzyme and thus alter the probability of a drug interaction.

If the drugs compete to a greater degree in someone with the particular genetic flaws researchers will study, the dose of the drug will have to be decreased more than expected. If the drugs compete to a lesser degree, the dose of the drug will have to be increased.

One situation in which this kind of change may have serious consequences is when patients take blood thinners. Dosing for drugs such as blood thinners requires an extremely close margin: Too little drug, and the patient can form a blood clot. Too much drug, and the patient can bleed to death. If patients take certain medications while taking blood thinners, researchers know the dose of the blood thinner must be reduced.

In this example, it’s unknown whether people with the genetic defects should have the same dosing adjustments for blood thinners and other drugs as people without the defect. By the end of the study, that’s something Tracy and his team expect to know.

Researchers will look at two enzymes in the body that most often have defects. They will look at the effects of 12 drugs on each enzyme. Since there are multiple—often three or four—defects on each enzyme, researchers will study dozens of combinations of drugs and genetic defects.

Researchers expect to find that people with the defect have different susceptibilities to an interaction and require a different adjustment of their medication from most people. “In fact, we expect to find that we must treat them differently than most of the population,” Tracy says.

Researchers are recruiting 150 subjects, some of whom will have the genetic defect. The researchers will compare those with the defect to those without the defect to see how the specified drugs interact. Researchers are also conducting test tube trials.