Genetics may explain as much as 30 percent of the differences in how people respond to painkillers like COX-2 inhibitors, but they paint only part of the picture, researchers said on Wednesday.

A study of 50 people given the drugs showed a surprising number of differences in how their bodies reacted to them, the researchers reported in the journal Gastroenterology.

The findings could eventually help scientists predict who should not take the COX-2 inhibitors, some of which have been shown to greatly raise the risk of heart attacks, said University of Pennsylvania School of Medicine researcher Dr. Garret FitzGerald, who led the study.

“Up until now we have chronically underestimated the very substantial differences in the way individuals respond to the same dose of the same drug,” FitzGerald said in a telephone interview.

The COX-2 inhibitors were originally designed to be a safer long-term treatment for arthritis and similar pain than aspirin and other analgesics. But they fell under a cloud when it was found they could raise the risk of heart problems.

Merck and Co. pulled its drug Vioxx from the market in September 2004 after a study showed it doubled the risk of heart attack and stroke in people who took Vioxx for at least 18 months.

The New Jersey-based drug maker has since been sued by more than 7,000 people who claim to have been harmed by Vioxx. The first trial ended in a hung jury last year.

In April, Pfizer Inc. suspended sales of its COX-2 inhibitor Bextra and now includes a strong “black box” warning for its COX-2 Celebrex.

FitzGerald has been studying the effects of the drugs and has found in the past they can cause long-term changes in the blood vessels, which may explain their heart disease risk. But he noted that only 1 percent to 2 percent of people who took the drugs were adversely affected.

Individual Differences

He figured there must be individual differences that make some people more susceptible than others.

He and colleagues tested 50 healthy adult volunteers, giving them either a placebo, Celebrex or Vioxx and then testing their blood, blood pressure and other reactions.

“One of the surprises in this study, where we put some of the people through the same protocol five times, is that there is substantial variation with a person on how they respond day to day. That can be due to a lot of potential sources, including environmental factors, that we don’t understand,” FitzGerald said.

He estimated 30 percent of the effects were due to genetic differences.

“Lots of genes could be important—genes that determine how you absorb a drug, variations in one gene involved in breaking down the drugs, variations in the way that you excrete a drug,” FitzGerald said.

“It would be foolish to think we could, for example, just have a test for one gene change and that would be enough to say ‘this drug’s for you’ or ‘you should avoid it.’”

It is more likely that scientists will devise a series of genetic and biochemical tests to see which drug a patient should take and which drug patients should avoid.

The crisis caused by the COX-2 inhibitors could finally spark the revolution in pharmacogenomics—the development of tailored drug treatments—that has been promised for years, he said.

“We are talking about selling a cheaper drug with the diagnostic tests that will say ‘This drug is for you.’”



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