The finding offers clinicians a way to identify patients who are likely to develop diarrhea as a side effect from taking these drugs, the researchers said. The discovery also has implications for people taking other drugs, since this pump controls the blood levels of many prescription drugs on the market.
This study is the first to show that a specific gene mutation disables the protein called ABCG2, preventing it from disposing of these drugs. ABCG2 pushes drugs out of the liver and into the intestine, from which it is excreted, according to the researchers. However, mutant ABCG2 can be less efficient at pushing cancer drugs out of cells in the intestine and a buildup of drug within these cells can cause diarrhea.
The finding was made during a study of patients being treated with the cancer drug gefinitib for non-small cell lung cancer.
“Gefitinib represents a new type of treatment called targeted therapy, which researchers hoped would avoid causing significant side effects,” said Sharyn Baker of the Department of Pharmaceutical Sciences at St Jude Children’s Research Hospital.
“Targeted drugs are designed to knock out specific molecules that occur in abnormal cells, while sparing normal cells. But our work showed that people with the ABCG2 mutation are at increased risk for side effects.”
Since diarrhea and skin toxicity limit the use of this drug in some patients, the researchers looked for a specific variation in the ABCG2 gene that could disrupt the function of the ABCG2 protein.
“Our finding also means that as targeted therapies become common in the years ahead it will be important to have a selection of such drugs so clinicians can choose those that are appropriate to the genetic makeup of the patient,” commented Sharyn Baker.