SCIENCE / MEDICINE : Susceptibility to Drug Dose Differs With Races : Pharmacology: Study finds dramatic variations in metabolism of medications by Asians and Caucasians.
In 1974, when Keh-Ming Lin moved from Taiwan to Seattle to finish his training in psychiatry, he was startled to learn that the dosage of anti-psychotic drugs given to schizophrenic American patients was often 10 times higher than the dose for Taiwanese patients with the same illness. Determining the reasons for the large disparity has since become a full-time research interest of Dr. Lin, now an associate professor of psychiatry at Harbor-UCLA Medical Center in Torrance.
During the last 15 years he has become a leading member of a small but growing number of scientists who are trying to learn why race appears to play an important role in determining a patient’s sensitivity to the effects of medications.
It is well known that flushing is a characteristic response to alcohol in many Asians. The reason is because the enzymes that metabolize alcohol do not work as efficiently in a high percentage of Asians--Chinese and Japanese in particular. This observation has led scientists to wonder whether Asians and others may respond differently to other drugs that affect the central nervous system.
Doctors on both sides of the Pacific have been aware for 40 years of the sometimes dramatic differences in drug dosage required to achieve a therapeutic effect in Asian and Caucasian patients. This may be one reason why drugs that have been established as safe in one country often must undergo new safety testing in other countries. But until recently, according to Lin, reports of ethnic differences were based only on surveys or anecdotal evidence rather than on systematic studies.
Now, however, research at centers around the world is beginning to demonstrate in a scientific manner that ethnic origin can strongly influence the response to therapeutic drugs. Ethnic groups under study have ranged from Greenlanders to South African blacks, but most comparisons so far have involved Asians.
While the work to date at Harbor-UCLA by Lin and pharmacologist Russell Poland has dealt solely with so-called psychotropic drugs for mental illness, investigators doing similar studies with other kinds of drugs have also begun to report striking differences.
For example, last year Dr. Hong-Hao Zhou and others at Vanderbilt University in Nashville found that men of Chinese origin have at least a twofold greater sensitivity than white American men to the effects of propranolol, a drug used to control blood pressure and heart rate.
Whether the reason for the different responses has a biological or a cultural basis or is a combination of both has not been clearly defined. Differences in diet and in attitude about the value of drug therapy, for example, could be cultural factors that may affect how individuals respond to treatment.
In one recent study conducted over a two-year period, Lin and Poland treated 13 Caucasian and 16 Asian schizophrenic patients with the drug haloperidol (Haldol). The results showed that Asian schizophrenic patients require significantly lower doses of the drug for the optimal treatment of their illness. Also, the researchers found that the minimum dose required to produce one of the principal side effects of such drugs was significantly lower in the Asians.
These side effects include muscle stiffness, tremors and restless leg syndrome, complaints which are not only uncomfortable but sometimes frightening. According to the researchers, a dosage that is excessive because the patient’s ethnic origin was not taken into account may help explain why some patients stop taking their medication and end up in psychiatric emergency rooms month after month.
A chief goal of the Harbor-UCLA studies is to find objective ways to factor in ethnic origin when determining an individual’s optimal dosage. This study is conducted at the medical center’s Research and Education Institute and funded by the California Department of Mental Health and the National Institute of Mental Health.
These studies and others conducted elsewhere are showing that while Asians--and presumably members of other ethnic groups--may be extra sensitive to one class of drugs, they may be less sensitive than other ethnic groups to another class of drugs.
In Lin and Poland’s study with Haldol, for example, they found higher concentrations of the drug in the blood of Chinese patients than in Caucasians given the same dose. This would indicate that Asians metabolized it slower and therefore needed a smaller dose in order to receive the desired effect. In the propranolol study at Vanderbilt, however, the metabolism rates between the two races were reversed.
The lower concentrations of the drug were in the Chinese patients, an indication that they metabolize propranolol faster than Caucasians. “The results point out the complexity of the issue,” Lin said. He explained that drugs are metabolized by enzymes in the liver and different drugs are metabolized by different enzymes. The enzymes that metabolize most drugs are controlled by genetic factors.
But differences in metabolic rates do not explain everything. Some drugs, because of their chemical composition, do not need to be metabolized. Yet the response to them by different ethnic groups is not uniform. One such drug is lithium, a medication used to treat mania and depression. According to Lin, reports have consistently shown that patients in Japan, Taiwan and China require lower levels of lithium than patients in Europe and the United States.
Lin and Poland have conducted studies indicating that part of the explanation for drug response differences lies in differences in the number or type of drug receptors in the brain. Receptors are structures in the brain and other tissues that drugs must attach themselves to--like a key fits into a lock--before a drug can become effective. Just as different drugs can be metabolized only by specific liver enzymes, receptors are custom-designed to accept only certain drug configurations. As with enzymes, the number and type of receptors is influenced by genetics.
Despite the growing evidence for a biological basis for the ethnic differences, the influence of culture and lifestyle cannot be ruled out. Earlier studies by other researchers indicated that differences in smoking and drinking habits, exposure to various drugs and illnesses that affect the liver and differences in the amount of body fat might explain variations in drug responses.
But the Harbor-UCLA scientists believe that their findings have been able to exclude these factors as having major influences. One way they attempted to rule out differences in lifestyles was by comparing Caucasians to American-born Asians (who could be assumed to have acquired some American habits) as well as with foreign-born Asians.
The scientists concluded that while the response to a drug by the American-born Asians tended to mimic that of foreign-born Asians, the differences were not significant. So far, the team has researched only two neuroleptic drugs--haloperidol (Haldol) and alprazolam (Xanax)--but they have plans to study others. Soon they hope also to begin similar kinds of studies to learn possible drug response differences among Caucasian, black and Latino patients.
