Drug sensitivity varies with ethnicity
by C. Wu

For centuries, people of different cultures have used opiates to relieve
pain. Now, it appears that sensitivity to the opiate codeine varies with
ethnic background, according to a recent study. These findings could help
doctors treat pain more effectively in different individuals.

Codeine's analgesic properties stem mainly from the body's ability to
metabolize it into morphine, a much more potent opiate, says Alastair J.J.
Wood of Vanderbilt University School of Medicine in Nashville. His research
indicates that further reactions contribute to the painkilling response.
Wood and his colleagues examined the effects of codeine in men of European
extraction and in Asian men. Both groups transformed codeine into morphine
similarly, but the Asian men experienced significantly weaker effects from
the drug.

Wood presented the findings this week at a meeting of the American Chemical
Society in Las Vegas.

"It's a nice piece of work," says Wendel L. Nelson of the University of
Washington in Seattle. Researchers had suspected that morphine is
responsible for the pain relief provided by codeine, but the current study
"is the clinical piece that really nails it down."

Previous studies have shown that some people lack an enzyme called CYP2D6
that chemically alters codeine into morphine. The same enzyme metabolizes
many drugs used to treat high blood pressure, heart arrhythmias, and
depression. About 8 percent of whites, 6 percent of blacks, and 1 percent of
Asians do not produce CYP2D6.

Currently, doctors tend to think that patients who don't respond to a
painkilling drug need higher doses. "Here's an example where a portion of
the population will get no effect, and increasing their dose a lot more will
still produce no effect," Wood says. "It's not that they're wimps or their
pain is worse than [that of] other people."

All of the people in the current study, 10 white men from the United States
and 8 men from China, possessed CYP2D6. Pain control is difficult to
measure, so the researchers monitored how codeine affected breathing, blood
pressure, and pupil dilation. Consistently, codeine affected the Chinese men
less than the U.S. men. Their bodies cleared morphine faster and increased
metabolism of codeine through enzymes other than CYP2D6.

No one knows whether the results shed any light on understanding addiction
to opiates, Wood says. At first, he hypothesized that people who abuse
codeine would possess CYP2D6, but his group realized that it would be
difficult to find appropriate subjects.

Scientists once thought that ethnic differences in rates of alcoholism might
have a biochemical basis. About half of Chinese and Japanese people flush
uncomfortably after consuming alcohol because they lack the enzyme aldehyde
dehydrogenase. Now, most scientists believe that social factors account for
the alcoholism difference.

Not many researchers consider ethnicity when testing drugs, Wood says. Based
on clinical studies of a "small, homogeneous population, we extrapolate
dosage and toxicity with breathtaking confidence to worldwide use." In the
case of codeine, the differences in metabolism aren't large enough to make
toxicity a concern, says Nelson.

Knowledge of the important enzymes involved in metabolism, however, does
spur drug companies to screen potential compounds very early, he says. "If
the company is going to invest money in developing a drug, it wants to know
if it won't work in a large percentage of the population."

References:

Wood, A.J.J. 1997. Pharmacogenetic and ethnic differences in opiate
response. Meeting of the American Chemical Society. Las Vegas.

Sources:

Wendel L. Nelson
Department of Medicinal Chemistry
University of Washington
Seattle, WA 98195

Alastair J.J. Wood
Department of Pharmacology
Vanderbilt University School of Medicine
Room 552A, MRB
Nashville, TN 372326602