Drug Reaction in the Family Tree

The body’s ability to process drugs is influenced, like so many things, by our genes. Our genetic makeup controls how quickly or slowly the liver breaks down medications, as well as how effectively they’re transported throughout our body. Every step in the sequence determines how much of a drug our bodies absorb.

If we metabolize certain drugs too slowly, the medication will build up in the bloodstream. A standard drug dose might be too much for some patients, and the side effects magnified. On the flip side, people who metabolize medications too quickly may not benefit from a standard dose, says Richard Weinshilboum, a pharmacogeneticist at the Mayo Clinic in Rochester, Minnesota.

One of the earliest discoveries of gene-drug interactions came in 1989 when Weinshilboum discovered that reactions to certain drugs, called thiopurines, could be inherited (thiopurines are used to treat children with the most common type of leukemia). Children who can't metabolize these drugs may have an adverse reaction if they take them.

"If your body can't metabolize the drug it's like getting an overdose," Weinshilboum says.

Today, a laboratory test can tell doctors which patients should and should not take thiopurines. The field of pharmacogenomics uses all 22,000 genes or so to tailor a drug and its dose to an individual's genetic makeup. Such information can predict how patients will react to certain drugs, which can help minimize bad reactions and maximize a drug's effectiveness. Research has found that a gene called CYP2D6 plays a role in the way tamoxifen is metabolized in women with estrogen receptor-positive breast cancer. Doctors can use this information to identify women who might respond best to the hormone therapy, although its routine use is still controversial. However, most cancer drugs are still used without pharmacogenetic guidance.

On the horizon are laboratory tests to predict which individuals will experience chemotherapy-induced long-term and late effects, such as hearing loss, cardiac toxicity and neuropathy. Eileen Dolan, a professor of medicine at the University of Chicago, is working to identify genetic markers to make such predictions.

"These patients can have a poor quality of life, or may need their chemotherapy dose reduced, which could compromise outcome," Dolan says.

She and her colleagues presented research at the annual meeting of the American Society of Human Genetics last October showing that similar genetic variants were associated with neuropathy after paclitaxel. Dolan's team hopes to use the information to identify new agents to treat or prevent neuropathy. Although using genetic markers to identify patients at risk for neuropathy is still unrealized, "the technology is advancing quickly," Dolan says.