Professional Documents
Culture Documents
It is now well documented that substantial disparities exist in the quality and quantity of
medical care received by minority Americans, especially those of African, Asian and Hispanic
heritage. In addition, the special needs and responses to pharmaceutical treatment of these
groups have been undervalued or ignored. This article reviews the genetic factors that underlie
varying responses to medicines observed among different ethnic and racial groups. Pharmaco-
genetic research in the past few decades has uncovered significant differences among racial and
ethnic groups in the metabolism, clinical effectiveness, and side-effect profiles of many clinically
important drugs. These differences must be taken into account in the design of cost management
policies such as formulary implementation, therapeutic substitution and step-care protocols.
These programs should be broad and flexible enough to enable rational choices and individu-
alized treatment for all patients, regardless of race or ethnic origin. (J Natl Med Assoc. 2002;
94:1-26.)
Key words: race * ethnicity* care services to minorities in the United States.'
pharmaceuticals * Of greater significance is the finding that these
pharmacogenomics disparities still exist even after adjustment for
differences in socioeconomic status, insurance
The recent report of the Institute of Medi- coverage, income, age, comorbid conditions,
cine (IOM), "Unequal Treatment: Confronting expression of symptoms, and access-related fac-
Racial and Ethnic Disparities in Healthcare," tors. These disparitiiss are not confined to any
illustrates in eloquent scientific detail that ra- one aspect of the health care setting, and can
cial and ethnic disparities in health care do even be found in the delivery of pharmaceuti-
exist and are prevalent in both the treatment of cal services, which are under increasing cost
medical illness and in the delivery of health control measures.
Implicit in this transaction is the ultimate
outcome of increased morbidity and mortality
© 2002. From the Health Policy Committee, Board of Trustees, Na- for African Americans and other minorities.
tional Medical Association, Washington, DC; and Scientific Affairs,
National Pharmaceutical Council, Reston, Virginia. Requests for re- This is mostly due to a diminished quality of
prints should be addressed to Dr Richard Levy, National Pharmaceu- medical care and health services, but also due
tical Council, 1 894 Preston White Drive, Reston, VA 20191. to a predilection to avoid using better quality
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 1
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
but higher costing pharmaceuticals in the treat- care models bent on cost containment has ad-
ment of African American and other minorities versely affected African Americans and minor-
by practitioners and health care institutions. ities.9
The conscious or unconscious decision by Publicly funded managed care plans, espe-
health care providers to withhold needed phar- cially Medicaid HMOs, may paradoxically re-
maceuticals and services from minorities is duce access to health care services for minori-
most notable in several key diseases. Studies in ties.9 A distressing outgrowth of these efforts to
cancer patients demonstrate that chemothera- contain costs in public insurance plans is the
py2 and analgesic therapy3 are more likely to be emergence of new state laws requiring generic
given to nonminorities. African Americans with drug substitutions for Medicaid recipients. Ef-
HIV disease are less likely to receive antiretro- fective October 1, 2002, in New York and other
viral agents,4 prophylaxis for Pneumocystis pneu- states, Medicaid patients will have to use ge-
monia and protease inhibitors compared with neric drugs in lieu of brand name drugs as a
nonminorities.5 In the area of cardiovascular matter of law, if such drugs have been deter-
care, there are clear differences in treatment mined to be "therapeutically equivalent." Ex-
regimens after coronary angiography, not re- emptions can be sought by persons or entities
lated to clinical factors.6 As reported elsewhere providing a valid study showing that the ge-
in this publication, studies have shown that Af- neric is less effective than the brand, has unto-
rican Americans and Hispanics receive fewer ward outcomes or adverse side effects, or a
antidepressants for clinical depression, and are potential negative impact on a recipient within
relatively under-treated with analgesics for pain a special population. This will impose barriers
from fractures or postoperative pain.7 African that busy health care providers can seldom
American and Hispanic patients with severe overcome. It also imposes an additional duty
pain of any cause are less likely than White and obligation upon health care institutions
patients to be able to obtain commonly pre- that serve these patients to monitor outcomes
scribed pain medicine because pharmacies in in using generic drugs on "all comers."
predominately non-White communities do not There is good evidence to show that thera-
normally carry adequate stocks of opiates.8 peutic substitution of drugs within the same
In assessing potential sources of disparities class places minority patients at greater risk.
in health care, the 2002 IOM report identified This is because effectiveness and toxicity can
patient-level, provider-level and health care sys- vary among racial and ethnic groups. Physi-
tem-level factors that might play a role beyond cians and managed care plans must be more
access-related causes of disparities. Patient-level alert under these new "formulary laws" for atyp-
and provider-level attributes were felt to be ical drug responses or unexpected untoward
largely based on racial attitudes, discrimina- side effects when treating patients from racial
tion, bias, stereotypes, and clinical uncertain- and ethnic minority groups. Dosage adjust-
ties that exist in the United States. This is re- ments might be necessary in using generic
flected in their conclusion "that much of drugs as therapeutic substitutions in untested
American social and economic life remains or- racial and ethnic groups. There is a distinct
dered by race and ethnicity, with minorities possibility of a toxic accumulation of such
disadvantaged relative to Whites." drugs from slower metabolism, or the need for
Health care system-level factors, however, medical service substitutions to supplement the
can be influenced and modified by govern- ineffective generic drugs in some racial and
ment through appropriate public policy. The ethnic and minority groups. Either outcome
current evolution in the organization, financ- will demand a greater use of health system
ing and delivery of health care services, includ- resources and thus obviate the original pur-
ing pharmaceutical services, toward managed pose of cost containment.
2 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 3
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
among racial and ethnic groups in the metab- acetylators compared to 7 to 34% of Chinese
olism, clinical effectiveness, and side effect pro- and Japanese.
files of therapeutically important drugs. Most Polymorphisms in drug targets and proteins
studies have concentrated on cardiovascular involved in disease progression can be major
agents (beta-blockers, diuretics, calcium chan- determinants of drug efficacy. Polymorphisms
nel blockers, and angiotensin-converting-en- in the gene encoding the serotonin receptor
zyme inhibitors) or central nervous system alter response to clozapine and antipsychotics.
agents (antidepressants and antipsychotics). Polymorphisms in apolipoprotein E (Apo E), a
Analgesics (acetaminophen, codeine), antihis- protein involved in cholesterol homeostasis, al-
tamines, and alcohol are other pharmacologic ter the risk of developing Alzheimer's disease
compounds with varying effects among differ- and the response to tacrine treatment. Tacrine
ent racial and ethnic populations. Most of the is less effective in individuals carrying a partic-
research applies to African Americans, Asians, ular Apo E polymorphism that is more preva-
and Whites. Fewer studies have specifically tar- lent in African Americans and Africans (20% to
geted Hispanics who, according to the 2000 US 30%) than among Asian populations (5% to
Census, are now the largest racial or ethnic 10%).
group after Whites.
Implications
Genetic Polymorphisms Polymorphisms may influence a drug's ac-
Polymorphisms are naturally occurring vari- tion by altering its pharmacokinetic (absorp-
ants in the structures of genes and the products tion, distribution, metabolism, excretion) or
they encode. The relevant gene products here pharmacodynamic (effect on the body) prop-
are drug metabolism enzymes, receptor pro- erties. Clinically, there may be an increase or
teins, and other proteins involved in drug re- decrease in the intensity and duration of the
sponse or disease progression. Polymorphisms expected drug effect and substantial dosage
occur in all human genes, but only some of
adjustments may be necessary for individuals
from different populations. Importantly, be-
them alter the functioning of the gene prod- cause different agents of the same drug class
uct, and only some of these vary significantly in are often cleared by different metabolic path-
frequency among different populations. Poly- ways, drugs of a class may differ in their suscep-
morphisms in drug metabolism enzymes have tibility to genetic differences in metabolism. In
been intensively studied because they affect addition, the pathophysiology of disease may
many drugs across different drug classes. The differ among racial groups (e.g., hypertension)
two most important polymorphisms for this and some agents will be more effective than
discussion affect the metabolism of antiarrhyth- others in a given racial group.
mics, antidepressants, beta-blockers, neuro-
leptics, opioids, barbiturates, and benzodiaz- Recommendations
epines. A third polymorphism affects Attention should be paid to the need to in-
metabolism of caffeine and isoniazid. This poly- dividualize drug therapy for specific popula-
morphism was first studied when isoniazid was tion groups by health care policy makers and
introduced for the treatment of tuberculosis. providers. The following recommendations
Patients were classified as fast or slow elimina- can have positive benefits on the quality of care
tors of isoniazid on the basis of a genetically for racial and ethnic subpopulations and may
determined defect in their ability to metabolize also help to control health care costs.
the drug. The proportions of rapid acetylators
and slow acetylators vary considerably in differ- 1) Health care institutions should limit
ent populations: 52 to 62% of Whites are slow the practice of therapeutic substitution,
4 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 5
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Prior authorization by Medicaid programs is fected. Patients in these groups receive less
widespread. Prior authorization is sometimes intensive medical treatment than the nation as
used to limit access to newer generation phar- a whole, including fewer vaccinations, less drug
maceuticals and represents an administrative therapy for pain, fewer antiretroviral drugs for
burden on physicians and their staff who must HIV/AIDS, and fewer antidepressants. African
obtain clearance from Medicaid before pre- American and Hispanic patients with severe
scribing certain medications. In addition, for pain are less likely than White patients to be
certain subpopulations that have a different able to obtain commonly prescribed pain med-
response to medication or who have different icines, because pharmacies in predominantly
symptoms, such limitations may produce sub- non-White communities do not carry adequate
optimal, adverse, or unexpected responses. stocks of opiates. Other studies have revealed
Health care plans have turned to formularies in under-treatment of Hispanics and African
an attempt to manage their drug costs but of- Americans for pain from fractures, inadequate
ten with unintended consequences. Studies
show that restrictive formularies can result in management of postoperative pain in non-
service substitution-that is, the replacement White patients, and a lower likelihood of cura-
of medications with medical services at a much tive surgery for cancer in African Americans
higher cost. Because of the strong association than in Whites of equivalent socioeconomic
with increased use of health care services, the status.7
policy of restricting formularies should be re- The demographic changes anticipated over
examined. The practice of tiered copay- the next decade magnify the importance of
ments-i.e., the policy of escalating copay- these disparities. According to the 2000 census,
ments for nonformulary drugs of substitution racial groups other than 'White' make up 33%
of brand name for generic drugs-is formulary of the U.S. population (Fig. 1) .+ African Amer-
restriction in another guise. icans and Hispanics represent a growing per-
Disease management is an alternative strat- centage of the urban population in the United
egy to prior authorization and other policies States. These groups constitute the new urban
that limit access to pharmaceuticals, which en- majority in American cities such as Washing-
sures access to state-of-the-art pharmaceuticals ton, Detroit, and Los Angeles. Moreover, a dis-
while controlling overall costs. Disease manage- proportionate percentage of these Americans
ment benefits chronically ill patients, ensures in urban areas depend on Medicare and Med-
more appropriate use of medications, and low- icaid as their sole health care providers. Con-
ers unnecessary spending. sequently, these programs should not adopt
policies that ignore the special needs of a grow-
Effects of Restrictive Policies on Patients from ing percentage of the patient groups they are
Varied Racial and Ethnic Backgroundst intended to serve. Inappropriate policies re-
Disparities in the quality of medical care pro- garding the impact of race and ethnicity on
vided to patients of different racial and ethnic pharmaceuticals can have wide-ranging and po-
groups have been extensively documented.'0 tentially damaging implications.
Most studies have focused on African Ameri-
cans, but other studies have shown that His-
panic and Asian Americans are similarly af- tThe classifications of race and ethnicity were different in the 2000
census than in earlier censuses. In 2000, almost seven million individ-
uals reported belonging to two or more racial categories. Ethnic origin
tWhile the meanings of the terms 'racial' and 'ethnic' continue to was considered to be a separate concept from race, so that people of
evolve, here 'racial' refers to genetically defined differences, while Hispanic origin could belong to any racial category. Hispanics made
'ethnic' refers to cultural differences. Thus, 'Hispanic' defines an ethnic up 12.5% of the total 2000 population. Of the 87.5% that were not
group that includes several different races. Hispanic, 79.0% were White.
6 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 7
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
perficial and are thought to be adaptations to there are differences in the prevalence of
climate and geography involving relatively few these determinants among different popula-
genetic changes. The loss of skin pigmentation tions. Research in the last 35 years has uncov-
among peoples living at high latitudes (the ered significant differences among racial and
'White race') is hypothesized to have been se- ethnic groups in their rates of drug metabo-
lected for by the requirement for exposure to lism, in clinical responses to drugs, and in
sunlight for the biosynthesis of vitamin D and drug side effects. African American and
hence the prevention of rickets. Skin color is White patients differ significantly in their re-
determined by melanins whose production is sponses to beta-blockers, ACE inhibitors, and
hormonally regulated via the MClR (melano- diuretics used either alone or in combination
cortin-stimulating hormone receptor) gene. for the treatment of hypertension. Chinese
Multiple polymorphisms in MC1R that have are considerably more sensitive than Whites
evolved relatively recently may explain much of to the effects of the beta-blocker propranolol
the variation in skin color.'3 on heart rate and blood pressure. Asians are
more likely to require lower dosages than
Genetic Variation within and between Whites of a variety of different psychotropic
Populations drugs, including lithium, antidepressants,
Most human genetic variation antedates the and antipsychotics.
migration of modem humans out of Africa. Put Race is an imprecise substitute measure of
differently, most genetic variation occurs within these genetic differences. When relevant to a
any given population rather than between popu- particular drug, race and ethnicity should be
lations. An average population from anywhere in considered along with other factors such as
the world includes 85% of all the variation in age, gender, diet, smoking status, and other
autosomal genes (genes on chromosomes other factors that modify, often only slightly, the
than the sex chromosomes). Differences among risk of disease or drug response. Practicing
populations from the same continent contribute physicians treating individual patients and,
6% of genetic variation, and differences among equally importantly, institutional policy mak-
populations from different continents contribute ers should be sensitive to the implications of
9% to 13%.14 racial and ethnic differences in drug therapy.
The Uses of Racial Categorization in Medicine Restrictive policies may pose greater degrees
Individual genetic polymorphisms change of risk for patients of different racial and
gradually in prevalence across continents and ethnic backgrounds. A clear message of the
do not separate populations into clearly de- recent findings in this field is that racial and
marcated groups that correspond to the pop- ethnic differences must be factored into for-
ular idea of race. Physical traits commonly mulary selection and prescribing decisions
associated with 'racial' groups-skin and hair on an individual basis. Otherwise, these
color, facial features, etc.-are superficial groups may be disadvantaged by institutional
characteristics that have little relevance to pharmaceutical policies that restrict individ-
the response to drugs or to the progression ualized drug therapy.
of complex diseases such as diabetes mellitus,
coronary heart disease, and so forth.14"15 INTERPLAY OF GENETIC, ENVIRONMENTAL,
What, then, is the scientific rationale for race AND CULTURAL FACTORS
continuing to occupy such an important The factors contributing to variability in
place in the medical consciousness? Geneti- drug response are complex and interrelated
cally determined differences in the response (Fig. 2). Differences in drug response among
to drugs do exist among individuals, and racial and ethnic groups are determined by
8 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
/ | ~~~Systemic circulation|\
{ \ | ~~~~~~~~Distribution|
{
Metabolism
\ flion Excretion
\ | ~ ~ Site of action|/
ENVIRONMENTAL FACTORS
Climate
Parasites
Pollutants
Smoking
Alcohol
Drugs
Figure 2. Factors contributing to variability in drug response. Adapted from Poolsup et al. (2000).16
genetic, environmental, and cultural (mean- mented in which inherited individual traits
ing, in this context, psychosocial) factors. were implicated in atypical, exaggerated re-
These factors may operate independently of sponses to drugs, novel drug effects, or lack of
one another, or they may interact dynamically effectiveness of drugs.'7
and synergistically. The genetic makeup of an individual may
change the action of a drug in a number of
Biological Factors ways as it moves through the body. Genetic
Age and sex, of course, affect drug response, factors may influence a drug's action by alter-
but the primary biological factor we are con- ing its pharmacokinetic properties (absorp-
cerned with is genetics. Studies of twins and tion, distribution, metabolism, excretion) or
blood relatives have shown that genetic factors pharmacodynamic properties (effect on the
are the major biological determinants of the body). Clinically, there may be an increase or
normal variability of drug effects and are re- decrease in the intensity and duration of the
sponsible for many differences in pharmaco- expected typical effect of the drug.
logic activity among normal subjects studied The study of genetically determined varia-
under carefully controlled environmental con- tions in drug response is called pharmacoge-
ditions. Over 100 examples have been docu- netics. Variations in drug response are caused
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 9
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
by gene polymorphisms. Genes are considered dence has accumulated that a G6PD deficiency
to be functionally polymorphic when variants protects against infection with P. falciparum, the
of the gene exist stable in the population, one parasite that causes a fatal form of malaria.
or more of which alters the activity of the gene Variants in G6PD that lead to reduced enzyme
product (which is typically a protein such as a activity occur much more frequently in coun-
drug metabolizing enzyme or a drug receptor). tries in which malaria is or was endemic (see
Pharmacogenetics has traditionally meant the Fig. 3). There are more than 30 polymorphisms
study of polymorphisms in individual genes. that result in G6PD deficiency and hence pro-
This field has now broadened into pharmacog- tection against P. falciparum. These polymor-
enomics, which examines the effects of the en- phic variants, and the ancestral strain of P.
tire genome, i.e., all of the genes, on drug falciparum, arose between about 3,000 and
response. In pharmacogenomics, large arrays 10,000 years ago, coincident it is believed with
of genes are studied in parallel, so that the the spread of farming, which provided condi-
entire spectrum of genes that determine the tions conducive to the spread of malaria.2'
response to a particular drug can be examined Skin pigmentation is also the result of an
at one time. interaction between genetic and environmen-
Environmental Factors tal factors. Light-skinned individuals are sub-
ject to drug-induced phototoxicity after ingest-
Environmental factors-diet, climate, smok- ing certain drugs.22-24
ing, alcohol, drugs, pollutants'6-may cause
wide variations in drug response within an in- Cultural Factors
dividual and even wider variations between Cultural or psychosocial factors, such as the
groups of individuals. Several of these factors attitudes and beliefs of an ethnic group, may
can operate simultaneously in the same indi-
affect the effectiveness of, or adherence to, a
vidual, thus affecting the processes of drug ab-
sorption, distribution, biotransformation, ex- particular drug therapy. Cross-disciplinary
cretion, and receptor interaction in different fields-pharmacoanthropology, medical an-
ways and to different degrees.'8 thropology, and cultural psychiatry,-have
Differences in diet may significantly alter the emerged to study these issues. Pharmacoan-
metabolism rate or drug blood levels among thropology studies interethnic differences in
different ethnic populations. Studies compar- drug responses by examining population char-
ing the metabolism of antipyrine between acteristics in social and genetic terms and using
Asian Indians in rural Indian villages and In- methods suitable for pharmacological investi-
dian immigrants in England demonstrated that gation of large numbers of subjects.25 Medical
as immigrants adopted the lifestyle and dietary anthropologists study the effects of a patient's
habits of the British, their drug metabolism perception of illness and disease in a cross-
accelerated. Similar findings have been ob- cultural context to determine the role that eth-
served among Sudanese and Western Afri- nic and cultural perceptions and beliefs play in
cans.'9 the patient's adherence to or understanding of
A striking example of the interplay of envi- medical therapy or drug treatment. For exam-
ronmental and genetic factors is found in the ple, the physician's ability to treat a patient
relationship between malaria and expression of effectively may be impeded by the patient's
the gene G6PD in red blood cells. G6PD en- culturally determined perception of the mean-
codes an enzyme (glucose-6-phospate dehydro- ing of his or her illness.26 Cultural psychiatry
genase), a deficiency of which leads to anemia focuses on the interaction of culture and psy-
if the person is exposed to certain foods (e.g., chiatric disorders, and includes cross-cultural
fava beans) or drugs (e.g., primaquine).2O Evi- differences in symptoms and diagnoses, and
10 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICAlS
correspond
~~~~Ifro
E_m_
Luzat
ths in whcmari
to~~~r
& Noar (2001 21_
is (or was enei (rgin enei fr maai no iniae onmp._dpe
variations in dose response to psychotropics sponses agree that these effects are real and
among different ethnic groups. can be documented through case studies or
Studies have consistently shown that Afri- epidemiological surveys. However, it is difficult
can-American patients are more likely to be to design large, controlled clinical trials to iso-
overdiagnosed as having a psychotic illness late any of these factors and determine its ef-
and are more likely to be treated with neuro- fect as an independent variable on drug re-
leptics regardless of diagnosis.'1927 African sponse in a particular ethnic group. The
Americans are also more likely to be placed complex interrelationships of environmental
on implanted or periodically injected rather and cultural factors make them less readily
than oral medications, reflecting physicians' amenable to reproducible results, so that re-
concern about adherence. There is also evi- search in this field so far has concentrated on
dence from large-scale drug trials that the identifying genetic factors.
placebo response is greater among non-
Whites. Other studies have shown that the GENETIC POLYMORPHISMS IN DRUG
perception and report of adverse effects of METABOLISM, DRUG TARGETS, AND DISEASE
drugs are influenced by patients' culturally PATHWAYS
determined beliefs.'9 Overview
Investigators who study the effects of cultural Polymorphisms are naturally occurring variants
or psychosocial factors on differing drug re- in the structures of genes and the products they
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Table 1. Mechanisms and Examples of Clinically Relevant Genetic Polymorphisms Influencing Drug Metabolism and
Effects
Mechanism Example Pharmacogenetic effect
Drug metabolism Cytochrome P450 Enzyme "Poor metabolizer" phenotype in -25% of all drugs
CYP2D6
Drug target Serotonin (5-HT2A) receptor Altered binding of the atypical antipsychotic
clozapine
Disease pathway Cholesterol esterase transport Atherosclerosis progression and response to the
protein (CETP) HMG-CoA inhibitor pravastatin
Source: Kleyn & Vesell (1998).29
encode. The gene products are usually pro- before their clearance from the bloodstream
teins that interact in some way with drugs. Poly- and elimination from the body. Biotransforma-
morphisms affecting the response to drugs can tion is most commonly a process of oxidation
occur in genes involved in one of three pro- or of acetylation or methylation (Table 2).
cesses or mechanisms- drug metabolism, drug Most oxidation is performed by one of several
targets, and the disease pathway. An example oxidative enzyme systems associated with cyto-
of each of these three mechanisms is shown in chrome P450. These enzymes are now referred
Table 1. Of the three mechanisms, polymor- to by their genetic names (CYP2C9, CYP2CJ9,
phisms in drug metabolism genes are consid- CYP2D6, etc.), although they were originally
ered most important because they act across referred to by the test drugs (or 'probe' drugs)
classes of drugs, whereas a mutation in the whose metabolism they controlled: debriso-
gene encoding a drug target (such as a recep- quine or sparteine for CYP2D6, mephenytoin
tor protein) will only affect the class of drugs
that interacts with that target. for CYP2C19, and phenytoin for CYP2C9.
Although there are polymorphisms in all Other important drug metabolism genes are
genes controlling drug effects, they do not nec- the acetylation gene NAT2 (encoding Nacetyl-
essarily alter drug response and do not neces- transferase 2) and the methylation gene TPMT
sarily show significant variation among popula- (encoding thiopurine methyltransferase).
tions. In this discussion, we shall focus on those Common polymorphisms in drug metabo-
polymorphisms known to have clinically impor- lism genes have received the most attention
tant roles and to vary among populations. because they affect the metabolism of many
clinical important drugs and large numbers of
Polymorphisms of Drug Metabolism patients. Polymorphic variants in these genes
Most drugs are chemically modified (bio- alter the activity of the encoded enzyme most
transformed) and thus inactivated in the liver often by reducing it, sometimes by eliminating
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Table 3. Drugs Metabolized by CYP2D6 tabolizer phenotype are listed in Table 4. Dif-
Drug class Drugs ferences in the frequency of the CYP2D6 poor
metabolizer phenotype have been demon-
Psychotropic strated among different racial and ethnic
Antipsychotics Haloperidol, perphenazine,
thioridazine, fluphenazine, groups and among subpopulations of the same
clozapine, risperidone, racial group.
chlorpromazine Polymorphisms in CYP2C19 affect the me-
Antidepressants Amitriptyline, clomipramine, tabolism of mephenytoin, hexobarbital, diaze-
desipramine, fluoxetine,
imipramine, maprotiline, pam, omeprazol, and many other drugs (Table
nortriptyline, paroxetine 5). Some drugs, e.g., amitriptyline, clomipra-
Cardiovascular mine, propranolol, can be substrates for both
Anti-arrhythmics Propafenone, flecainide, CYP2C19 and CYP2D6, indicating that there is
sparteine, quinidine
Beta-blockers Propranolol, timolol, redundancy and overlap between these two sys-
metoprolol, labetalol tems.
Antihypertensives Debrisoquine, clonidine Polymorphisms in NAT2, the gene encoding
Miscellaneous Codeine, nicotine, N-acetyltransferase 2, affect metabolism of caf-
methoxyamphetamine
feine and other drugs, including isoniazid (Ta-
Source: Poolsup et al. (2000). 16 ble 2). NAT2 polymorphisms were first studied
when isoniazid therapy was introduced for the
treatment of tuberculosis. Patients were classi-
it, and occasionally by enhancing it. This leads fied as fast or slow eliminators of isoniazid on
to differential rates of metabolic clearance of the basis of a metabolic defect in their ability to
the drug metabolized. Those individuals who metabolize the drug. This polymorphism is es-
do not metabolize a certain drug efficiendly are pecially important in the study of racial and
called "poor metabolizers" (PM), as opposed to ethnic drug responses because the proportions
normal or "extensive metabolizers" (EM). of rapid acetylators (RA) and slow acetylators
The effect of the poor metabolizer pheno- (SA) vary considerably in different ethnic
type is to increase the exposure to the active and/or geographic populations.'7
drug by increasing the peak concentration in
the blood and the time to clearance. This is the Polymorphisms of Drug Targets
equivalent of an overdose of the drug. The Drug targets include hormone or neuro-
efficacy is not enhanced because dosages are transmitter receptors, specific enzymes, and
normally targeted to have optimum efficacy, ion channels (Table 6). Many of the genes
i.e., further increasing the dose does not fur- encoding drug targets exhibit polymorphisms
ther increase the effect. Adverse effects are in- that alter their sensitivity to particular medica-
creased, however, because dosages are nor- tions. Examples include: polymorphisms in
mally targeted to be close to the bottom of the beta-adrenergic receptors and their sensitivity
threshold where adverse effects begin to ap- to beta-agonists in asthmatics; angiotensin-con-
pear. In sum, the poor metabolizer phenotype verting enzyme (ACE) and its sensitivity to ACE
effectively decreases the therapeutic ratio (effi- inhibitors; angiotensin II TI receptor and vas-
cacy:toxicity) of the drug.29 cular reactivity to phenylephrine or response to
Polymorphisms in CYP2D6 are among the ACE inhibitors; sufonylurea receptor and re-
clinically most important because so many sponsiveness to sufonylurea hypoglycemic
drugs are metabolized by this pathway, includ- agents; and 5-hydroxytryptamine receptor and
ing antiarrhythmic, antidepressant, beta- response to antipsychotics such as clozapine.29
blocker, neuroleptic, and opioid agents (Table The effect of a drug receptor mutant that
3). The implications of the CYP2D6 poor me- reduces binding of the target drug is to reduce
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
the efficacy of the drug and, hence, the thera- 7% in Chinese populations, 10% in other Asian
peutic ratio. Unlike the poor metabolizer phe- and American Indian groups, and 20% to 30%
notype of drug metabolizing genes, there is no in African Americans and Africans.3' Tacrine,
direct effect on the incidence of adverse ef- the cholinomimetic drug used to treat Alzhei-
fects. mer's disease, is more effective in individuals
who do not carry the E4 polymorphism. Fur-
Polymorphisms of Disease Pathways thermore, lorazepam-induced memory impair-
Genetic polymorphisms that underlie dis- ment is greater in elderly individuals carrying
ease pathogenesis can be major determinants E4.31 These polymorphisms also appear to af-
of drug efficacy (Table 7). fect response to lipid-lowering drugs, including
Apolipoprotein E is an example of protein fibrates and statins, but the data are complex
that affects disease progression and the action and a clear interpretation has not yet emerged.
of drugs, and that exists in several polymorphic
variants. Apolipoprotein E is a circulating and RACIAL AND ETHNIC VARIATION IN
tissue protein involved in cholesterol ho- POLYMORPHISMS IN DRUG METABOLISM
moeostasis and other functions. Common ge-
netic polymorphisms affect both the lipid and How Genetic Polymorphisms Are Expressed in
receptor associations of apolipoprotein E, al- the Population
tering lipid profiles and correlating with dis- Polymorphisms are alterations in the genes
eases linked to lipid metabolism-particularly that potentially alter the activity of the gene
cardiovascular disease, but also Alzheimer's dis- product-in this instance, an enzyme involved
ease. The distribution of apolipoprotein E poly- in drug metabolism. If the gene product re-
morphisms varies among populations. The fre- tains some activity, the genetic polymorphism is
quency of the E4 polymorphism is about 5% to referred to as an active allele ('allele' is the
genetic term for a mutant form of a gene; the
Table 5. Drugs Metabolized by CYP2C19 native form of a gene is called the wild type).
There are also inactive alleles that produce no
Carisoprodol Amitriptyline enzyme at all or a completely inactive enzyme.
Citalopram Clomipramine Less often, multiple copies of the wild type
Diazepam Hexobarbital gene or an active allele may occur, which re-
Mephenytoin Imipramine sults in greater than normal enzyme activity
Omeprazole Mephobarbital
Propranolol (referred to as the ultra extensive metabolizer
phenotype). Thus, many different polymor-
Source: Poolsup et al. (2000). 16 phisms can produce the same few end results:
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
an enzyme with normal activity, reduced activ- tions of two inactive alleles with each other or
ity, or no activity. Since humans have two cop- with an active allele.
ies of every autosomal gene, i.e., one from each
parent, either or both of the copies might be a Racial Variations in CYP2D6 and CYP2D19
wild type copy or any one of the polymorphic Polymorphisms
variants. The resulting phenotype, whether ex- The prevalence of the PM phenotype of both
tensive metabolizer or poor metabolizer, de- the CYP2D6 and CYP2C19 drug metabolism sys-
pends on which combination of two gene cop- tems in different populations is shown in Table
ies is present. 9-i.e., Table 9 shows phenotypic frequencies
This is illustrated in Table 8 for CYP2D6 and not gene frequencies. The prevalence of
polymorphisms. Combinations of the wild type the CYP2D6 poor metabolizer phenotype is in
gene and any of the several common active or the range of 0 to 2.1% in Asian populations
inactive alleles still produce the EM phenotype and in populations indigenous to the Asian
because sufficient wild type enzyme is pro- subcontinent, Egypt, Saudi Arabia, and Pan-
duced from the wild type gene copy. Thus, in ama (Table 9).
total 81.9% of the White population has the The CYP2D6 poor metabolizer phenotype is
EM phenotype, although this is the result of a more common in White populations (median
variety of genotypes. Combinations of the vari- prevalence 7.2%). The prevalence in Sub-
ous active and inactive alleles produce the poor Saharan Africa is greater than in Asian popula-
metabolizer phenotype. The prevalence of the tions but varies greatly, reaching 18.8% in the
PM phenotype in the White subjects studied in San bushmen. The prevalence in African Amer-
Table 8 is 11.4%, due in most part to combina- icans is 1.9%.
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
In contrast, the prevalence of the CYP2C19 Table 8. Many Different Genotypes Produce the Same
slow metabolizer phenotype is high in Asian pop- Few Phenotypes: Prevalence of the Most Common
ulations (median 15.7%) and in the Asian sub- CYP2D6 Polymorphisms among Unrelated Caucasian
Subjects
continent (17.6%) and low in Whites (median
2.9%-Table 9). The prevalence in African % of
Americans (18.5%) is higher than among Tanza- Genotype* Phenotype Population
nians (3.6%) and Zimbabweans (4.0%). The wild type / wild type EM 47.6
prevalence in Chinese populations refer to the wild type / active allele EM -
majority ethnic Chinese group (Han). However, wild type / inactive allele EM 34.3
wild type / amplified allele UEM 6.7
China is a multinational country with 55 ethnic active allele / active allele PM -
minorities in addition to the Han majority. The active allele / inactive allele PM 2.9
prevalence of the CYP2C19 poor metabolizer inactive allele / inactive allele PM 8.5
phenotype is significantly lower in some of these *Each individual has two copies of every gene- one from
groups than in the Han Chinese.33 each parent (with the exception of genes on the Y chromo-
some). The normal gene is called the wild type, and altered
Racial Variations in Acetylation versions are called alleles. An individual may have any
combination of wild type genes or mutant alleles. Active
The prevalence of the slow acetylator pheno- alleles are altered versions of the wild type gene that
type in various populations is shown in Table encode mutant CYP2D6 enzymes that retain partial activ-
10. It is roughly 50% in both the African Amer- ity. The common active alleles are CYP2D6 A and CYP2D6
L. Inactive alleles are versions of the gene that encode
ican and White populations (median 51% and CYP2D6 enzymes with little and sometimes no enzymic
58%, respectively). The prevalence in Asian activity. The common inactive alleles are CYP2D6 B and
populations is considerably lower (median CYP2D6 D (in this allele, the gene is deleted). In the L2
polymorphism, an active allele is present in amplified form,
22% in Chinese and 10% in Japanese). i.e., there are multiple copies of the allele; this leads to
more CYP2D6 enzyme being produced and hence the
CLINICAL RELEVANCE OF GENETIC UEM phenotype.
EM, extensive metabolism. PM, poor metabolism. UEM,
POLYMORPHISMS ultra-extensive metabolism.
It is important to determine whether a given Adapted from Linder et al. (1 997).32
polymorphism has clinical relevance in drug
therapy. Meyer poses four questions to deter-
mine the clinical importance of a genetic poly- tween the poor metabolizer and extensive me-
morphism:'7 tabolizer phenotypes-as is the case, for
example, with the psychotropic drugs desipra-
1) Does the polymorphic pathway of the mine and perphenazine. Second, pharmacoki-
drug result in a major difference between netic differences are relevant chiefly if the drug
the EM and PM phenotypes in the clear- has a small therapeutic index, e.g., isoprotere-
ance or elimination of the drug? nol, phenytoin, warfarin, clonidine, and quini-
2) Does the drug have a narrow therapeutic dine gluconate. Third, if physicians adjust drug
index? dosage based on the therapeutic effect (as is
3) Is the dosage of the drug individually usual with antihypertensive drugs), then pheno-
evaluated on the basis of the therapeutic typic differences are automatically corrected, al-
effect? though the physician may not be aware of any
4) Is the drug widely used by many physi- pharmacokinetic variation. Fourth, widely pre-
cians or only by a clinical specialist? scribed drugs such as beta-blockers or tricyclic
antidepressants have broader clinical implica-
First, polymorphisms only have clinical impor- tions because more patients in more population
tance when they result in large differences be- subgroups are affected.
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Table 9. Prevalence of CYP2D6 and CYP2C19 Poor Metabolizer Phenotypes in Various Populations
Poor metabolizer phenotype (%)
Population N Populationsa Median Range
CYP2D6
African (Sub-Saharan)b 6 3.4 1.8-18.8
Amerindianc 1 0
Asiand 8 0.5 0-2.1
Asian Subcontinente 1 0
Caucasianf 20 7.2 3.2-10.4
Middle East/North Africag 2 1.5 1.4-1.5
Polynesian (S. Pacific) 1 0
CYP2C 1 9
African (Sub-Saharan)h 3 4.0 3.6-1 8.5
Amerindian' 1 2.0
Asiani 6 15.7 5.1-23.6
Asian Subcontinentk 2 17.6 14.4-20.8
Caucasian' 12 2.9 1.3-6.1
Middle East/North Africam 1 2.0
Polynesian (S. Pacific) 1 13.6
aNumber of different populations. Where there were two or more studies of the same population (e.g., Chinese), the data
were pooled and the median percentage used.
bAfrican American, Ethiopian, Ghanaian, Nigerian, San (S. Africa), Tanzanian.
cCuna (Panama).
dChinese (China), Chinese (Singapore), Filipino (Saudi Arabia), Indonesian, Japanese, Korean, Malays, Thai.
eSinhalese.
fAustralian, Belgian, British, Canadian, Danish, Dutch, Estonian, French, German, Greenlander, Italian, Jordanian, New
Zealand, Polish, Russian (Estonia), Spanish, Swedish, Swiss, Turkish, US.
9E yptian, Saudi Arabian.
hAfrican American, Tanzanian, Zimbabwean.
'Inuit.
iChinese (Canada), Chinese (China), Filipino (Saudi Arabia), Indonesian, Japanese, Korean.
kIndian, Sinhalese.
'Canadian, Danish, Dutch, Estonian, French, Greenlander, Jordanian, Russian (Estonia), Spanish, Swedish, Swiss, US.
mSaudi Arabian.
Adapted from Poolsup et al. (2000).16
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Americans. Similarly, the response to the be- Table 10. Frequency of Poor Acetylator Phenotypes in
ta-blocker isoproterenol is greater in Whites Various Populations
than in African Americans. Conversely, the Poor metabolizer
antihypertensive response to the diuretic hy- phenotype (%)
drochorothiazide is greater in African Amer- Population N Populationsf Median Range
icans, while exposure to the calcium channel
blocker nifedipine is lower in Whites than in Blacka 4 51 42-65
Caucasianb 4 58 52-62
South Asians, Koreans, or Nigerians. Chinesec 7 22 13-34
The beta-blocker propranolol is more effective Japanesed 2 10 7-12
in reducing blood pressure and heart rate in Eskimoe 2 6 5-21
Chinese than in Whites. Patients in China are aBlack populations in East Africa, Nigeria, Sudan, and the
prescribed much lower doses of propranolol United States.
than patients in the United States and Europe bBritain, Canada, Germany, and United States.
because of a perception that Chinese people re- cChinese populations in Britain, Canada, Hong Kong,
spond to lower doses. Consistent with this, a study Mainland China, Singapore, Taiwan, and Thailand.
dJapan and the United States.
of the pharmacodynamics of propranolol found eAlaska and Canada.
that, at equivalent blood levels, Chinese men had fNumber of different populations. Where there were two or
greater sensitivity than White men to proprano- more studies of the same population, the data were pooled
and the median percentage used.
lol's effects on heart rate and blood pressure. Adapted from Wood & Zhou (1991).34
Paradoxically, the Chinese subjects metabolized
propranolol much more rapidly than the White
subjects; the total blood clearance for the Chi- and White populations. Black hypertensives ex-
nese was 76% higher, resulting in a substantially hibit enhanced sodium retention, a higher in-
lower area under the time-blood concentration cidence of salt-sensitive hypertension, ex-
curve (AUC). Clearance of propranolol was two panded blood volume, more frequent
times greater in Chinese subjects because of their proteinuria, and a higher prevalence of low
increased ability to metabolize the drug, resulting blood renin activity40 (although the majority of
in lower blood concentrations at similar doses. renin may reside in vascular tissue). The
Pharmacokinetic properties, therefore, do not T594M polymorphism in the epithelial sodium
explain the increased sensitivity of the Chinese. channel occurs in about 5% of Blacks and ap-
The mechanism for the increased sensitivity is pears to contribute to hypertension in these
not clearly determined, but could be because of a individuals.41 These factors may underlie some
greater suppression of renin in the Chinese pop- of the observed differences in the effectiveness
ulation.34 of various antihypertensive drugs in Black pop-
ulations. Ultimately, the choice of therapy must
Antihypertensive Drugs in Black Populations be tailored to the individual patient.
Hypertension is disproportionately preva- Although there is a long-standing discussion
lent in the Black population and is associated about the best type of antihypertensive drug to
with higher incidences of cerebrovascular and use in Black patients,42 African Americans re-
renal complications and left ventricular hyper- spond to drugs from all classes.'5'43 There is no
trophy. However, the overall risk of coronary specific class of antihypertensive drugs that cat-
artery disease in the Black male population is egorically should not be used based on race.
lower than in White males, particularly in Eu- Diuretics are frequently used to counteract in-
rope and the Caribbean, and to a lesser extent creased salt retention among Blacks, and recent
in the United States. findings suggest that the potassium-sparing di-
There are general differences in the patho- uretic amiloride is effective in controlling
physiology of hypertension between the Black blood pressure in patients with the T594M
18 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
polymorphism.4' Although some studies find evidence that Blacks may respond differently to
that beta-blockers, ACE inhibitors, and angio- different beta-blockers. Labetalol (a combined
tensin receptor blocking agents do not control alpha and beta-blocker) is significantly more
blood pressure in African Americans with the effective in controlling blood pressure in Black
same degree of effectiveness as in Whites, tar- patients than propranol or atenolol,4950 and
geted blood pressure levels can usually be evidence suggests that bisoprolol may have
achieved by adding a second antihypertensive comparable effectiveness in Blacks and
agent, such as a low dose diuretic.44'45'46'47'48 Whites.45 The Veterans studies also demon-
The Veterans Administration Cooperative strated that White patients responded better to
Studies showed that the beta-blocker propra- the ACE inhibitor captopril than Black pa-
nolol was less effective among Blacks than tients.3940 When a diuretic was added, this in-
Whites, and that this differential effect was terethnic difference was eliminated.
eliminated by addition of a diuretic. Nadolol, ACE inhibitors can be as effective in Blacks
atenolol, and penbutolol are also less effective as calcium channel blockers or diuretics, and in
in Black than in White hypertensives.45 There is some cases they may be more effective as a first
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Table 12. Racial and Ethnic Differences in Response to Central Nervous System Agents
Drug Comparison groups Exposure* Clinical response
Antidepressants
Clomipramine Asians, (Indian, Pakistani) vs. Greater in Asians (AUC) Higher incidence and severity
Whites (English) of side effects in Asians
Nortriptyline Japanese vs. American Greater in Japanese (AUC) N/A
Benzodiazepines
Alprazolam Asians vs. Caucasians Lower for Asians (CLs) N/A
Antipsychotics
Clozapine Korean Americans vs. N/A Clinically adjusted dose lower
Caucasians in Koreans, and higher rate
of anticholinergic side effects
Haloperidol Orientals (Chinese, Japanese, No difference Neuroleptic dose and optimal
Filipino, Korean, Vietnamese) response threshold lower for
vs. Caucasians Orientals
Chinese vs. Non-Chinese Higher mean blood levels in Clinically adjusted dose lower
(Caucasians, Hispanics, Chinese than in Americans for Chinese than for non-
Blacks) (when given same dose) Chinese
Caucasians vs. American-born Higher for Asians than for No difference in side effects
Asians vs. foreign-born Asians Caucasians (Cmax). Similar
(Chinese, Filipino, Japanese, for American-born and
Koreans) foreign-born Asians.
*Statistically significant differences in exposure, i.e., a measure of the blood concentration: either the area under the blood
concentration-time curve (AUC/, the peak blood concentration (Cmax), or systemic clearance (CLs).
N/A, not available.
Adapted from Poolsup et al. (2000)16 and Xie et al. (2001 ).38
line treatment. The AASK trial, which studied giodema, a potentially life-threatening side ef-
the progression of hypertensive kidney disease fect of ACE inhibitors, occurs 4.5-fold more
after treatment with an ACE inhibitor, a beta- often in African Americans.
blocker, and a calcium channel blocker, deter-
mined that the ACE inhibitor reduced the de- Cross-Racial Differences in Response to Central
cline in renal function to a greater extent than Nervous System Agents
the other drugs or classes.51'52 In hypertension Tricyclic Antidepressants. Tricyclic antidepres-
complicated by diabetic nephropathy and in sants (amitriptyline, clomipramine, desipra-
the presenceof proteinuria, ACE inhibitors are mine, imipramine, and nortriptyline) have a
first-line agents in Black as well as White pa- narrow therapeutic index and are metabolized
tients.40 However, since ACE inhibitors in lower by CYP2D6. Poor metabolizers and ultra exten-
doses can be less effective in Black patients, sive metabolizers may have clinical problems
higher doses may be required.53'54'55 when these drugs are taken at usually pre-
ACE inhibitors appear to be less effective in scribed doses. Poor metabolizers often develop
Black populations in the prevention and treat- elevated blood concentrations that may result
ment of heart failure in patients with left ven- in adverse effects. These side effects are rarely
tricular dysfunction. In the SOLVD trials, ena- life threatening, but they are sufficiently un-
lapril reduced the rate of hospitalization for pleasant that problems with patient compli-
heart failure in White but not in Black pa- ance ensue. Ultra-extensive metabolizers, on
tients.36 (Conversely, the beta-blocker carve- the other hand, may not respond to recom-
dilol is an equally effective treatment for heart mended doses because drug concentrations
failure in Black and White patients.56) An- are too low to be efficacious.
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
Clinical and pharmacokinetic studies have antipsychotic drug response have been con-
evaluated ethnic variations in dose response to ducted in Asian and White populations. These
clomipramine, desipramine, and nortriptyline. studies have in general found that, compared
In a study of clomipramine, the blood concen- with Whites, Asians respond to lower doses of
tration (AUC) was greater in Asians than in antipsychotic drugs and develop toxic side ef-
Whites after an equivalent dose, and Asians had fects at lower doses.'6'34 Although the data are
a higher incidence and severity of drug-related not entirely consistent, these results may be
side effects (Table 12). Similarly, the blood attributable to differences in pharmacokinet-
concentration of nortriptyline was found to be ics. Blood levels of haloperidol were higher in
greater in Japanese than in American Whites. Chinese or other Asians than in Whites in two
Pharmacokinetic studies with desipramine in studies (although not in a third). In these stud-
Asians and Whites have not produced consis- ies, the clinically adjusted dose of haloperidol
tent results. In studies of depressive patients, was lower for Chinese and other Orientals than
dosages of tricyclic antidepressants were lower for Whites (Table 12). Similarly, the clinically
for Asians than for White, and Asians re- adjusted dose of clozapine was lower in Korean
sponded to lower concentrations of desipra- Americans than in Whites. There was no differ-
mine or imipramine. ence between American-born and foreign-born
There are few reliable studies of cross-ethnic Asians in response to haloperidol (Table 12).
differences in drug disposition and response to There have been relatively few studies of the
tricyclic antidepressants in African and His- mechanisms responsible for the differences in
panic individuals. Hispanic patients have been clinical response to antipsychotics in African
reported to require lower doses of antidepres- American patients. In a study of trifluoperazine
sants and to experience more side effects when and fluphenzine, the pharmacokinetic param-
compared to Whites. The preponderance of eters did not differ between African Americans
the data suggest that, for a given dose of a and Whites. However, antipsychotic use (and
tricyclic antidepressant, African Americans often misuse) is more frequent in the African
show higher blood levels and faster therapeutic American population. African Americans have
response, but also more toxic side effects com- also tended to receive substantially higher
pared with Whites.57 doses of antipsychotics, perhaps because of di-
agnoses of more severe illness, but also because
Benzodiazepines of the stereotype that African Americans are
The benzodiazepine diazepam is an impor- more difficult to manage and are less compli-
tant drug affected by CYP2CI9 polymorphisms. ant.57 Rigorous studies are needed to delineate
However, there have been relatively few studies biological and cultural mechanisms that might
of ethnic differences in response to diazepam be responsible for these clinical practices and
or other benzodiazepines. Asian psychiatric pa- to characterize the pharmacokinetics and phar-
tients often require lower doses of diazepam, macodynamics in African American popula-
but this may be because of differences in body tions of these potent and potentially toxic sub-
fat rather than to genetic differences in drug stances.
metabolism.'6 The clearance of alprazolam, Other ethnic groups, such as Ashkenazi
which is metabolized by the CYP3A4 system, is Jews, may also respond differently to antipsy-
significantly higher in Whites than in Asians.38 chotic agents, especially with regard to the
side effects profile. Lieberman et al. found that
Antipsychotics clozapine, used to treat schizophrenia, was asso-
CYP2D6 polymorphisms affect the metabo- ciated with the development of agranulocytosis in
lism of antipsychotic drugs such as haloperidol 20% ofJewish patients, although this adverse re-
and clozapine. Most studies of ethnicity and action develops in only about 1% of chronic
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ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
22 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
differences in metabolism (diazepam, clonaz- search and its future impact on medicine. In
epam, nitrazepam) and drugs that are not (tria- the early decades of its existence, pharmacoge-
zolam, midazolam, lorazepam, temazepam, ox- netics focused on the enzymes responsible
azepam). Similarly some beta-blockers are drug metabolism. Differences in the genes en-
subject to differences in metabolism (metopro- coding these enzymes were inferred from dif-
lol, propranolol, timolol, labetalol, pindolol, ferences in the structure and activity of the
oxprenolol) and some are not (atenolol, nado- enzymes themselves, i.e., from phenotypic dif-
lol). While the cost containment strategy be- ferences. The frequencies of polymorphisms in
hind therapeutic substitution programs seems drug metabolism enzymes were observed to
practical, this policy may also be shortsighted, vary among different populations defined on
counter-effective, or clinically risky for patients the basis of race or ethnicity. Race or ethnicity
in different racial and ethnic groups. Unfortu- is, thus, a factor that changes the probability
nately, the pharmacokinetics of specific agents that an individual person will respond to a
in most drug classes has not yet been studied in given drug. However, "race" is an inaccurate
different racial and ethnic groups. Therefore, label for genetic variations that a given individ-
it is important that therapeutic substitution ual might or might not possess.
programs for patients of non-White racial and Two features of the genomics revolution,
ethnic groups be undertaken with extreme cau- with the Human Genome Project as its center-
tion. piece, have important consequences for the
Substitutions of antihypertensives drugs relationship between drug therapy and race or
within the same class may be particularly proW ethnicity. First, genetic variations are now de-
lematic for African-American patients. The as- termined by direct analysis of genes themselves
sumption that all beta-blockers are therapeuti- by determination of their nucleotide se-
cally equivalent is directly contradicted by the quences. Gene sequencing is now a rapid and
differences in clinical efficacy between pro- automated process. Second, the entire spec-
pranolol and labetalol for African American trum of genes that determine drug behavior
and White hypertensive patients. Hence, the and sensitivity can now be studied genetically.
policy of substituting within the class of all beta- That is, the effect of the entire genome on drug
blockers without consideration for clinical dif- behavior can now be determined rather than
ferences in racial and ethnic response might the effect of the individual gene-hence the
place African-American patients at a higher change from pharmacogenetics to pharmacog-
risk than Whites for receiving suboptimal ther- enomics. It is now possible to take a genetic
apy if propranolol were substituted for labe- 'fingerprint' of an individual and determine
talol. Interethnic differences between African precisely the presence of polymorphisms in the
American and White patients in response to genes known to be involved in drug interac-
antihypertensive treatment with beta-blockers tion. Instead of a person's race being a marker
also affect decisions about the cost-effective- for the possession of polymorphisms involved
ness of such treatment. in drug response, a genotypic profile can de-
Finally, the lack of research on drug re- termine with certainty whether or not the indi-
sponse differences among Hispanics, now the vidual possesses these polymorphisms.
nation's largest racial or ethnic minority group, In the future, drug treatment will be individ-
is of particular concern for the delivery of qual- ually tailored rather than race-based; however,
ity health care. the full impact of these changes will take many
years to unfold. Genetic fingerprinting using
The Future of Individualized Therapy DNA arrays is already practical, but the knowl-
Technological advances in the 1990s have edge base relating genomic variations to drug
changed the nature of pharmacogenetic re- response and disease progression has not been
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 23
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
developed. Observational studies are under ject to greater risks than those in other
way in which DNA fingerprints are being cor- groups if they are prescribed an "equiva-
related with data present in medical records lent" drug because substantial evidence
about medical history and drug response, and indicates that, even within a class, drug
it is expected that the medical records of an effectiveness and toxicity can vary among
entire country (Iceland) will be correlated with racial and ethnic groups. Institutional
genomic data. These developments will surely drug formularies and step-care protocols
have a profound impact on the ways in which should be broad enough to allow rational
new drugs are developed and used. choices of drugs and dosages for all pa-
Continuing research in pharmacogenomics tients, regardless of race or ethnic origin.
is likely to reveal significant and far-ranging 2) Pharmaceutical companies should con-
information regarding interindividual and tinue to include significant numbers of pa-
cross-racial differences in the actions of new tients from varied racial and ethnic back-
and existing drugs. These developments, along grounds in drug metabolism and clinical
with the increasing prevalence and influence of trials in instances where genetic polymor-
patients from a variety of races and ethnicities phism for that drug class is relevant. The
and the continued pressure to manage health vast majority of drug manufacturers test
care costs, will require programs having the and evaluate new pharmacological com-
dual objectives of cost control and individual- pounds on population subgroups, includ-
ized therapy for a racially and ethnically diverse ing racial and ethnic subgroups. This is
population of Americans. Balancing these two, likely to reveal drug actions and side effects
potentially opposing objectives will challenge specific to these groups, and may lead to
health policy makers in the coming decades. the discovery of therapies of specific advan-
tage to these populations.
CONCLUSIONS AND RECOMMENDATIONS 3) Health care providers should give indi-
As a result of advances in pharmacogenetics vidualized treatment to each patient and
research, as well as political and social changes resist the temptation to apply "cookbook"
affecting racial and ethnic groups, more con- drug therapy that does not take into ac-
sideration is being given to the need to individ- count racial or ethnic origin. For the
ualize drug therapy. Although the preceding practicing physician, each patient repre-
review is not an exhaustive account of clinical sents a unique and dynamic interaction
and pharmacological studies involving racial among determinants that are both ge-
and ethnic variation, it clearly emphasizes the netic and environmental. While it may be
range and scope of the problem. There can be impossible for a physician to anticipate
no mistaking the importance of this issue for all how a particular patient will respond in
health care providers. The following recom- every instance, it is imperative to individ-
mendations offer practical suggestions that can ualize therapy with respect to the appro-
have positive benefits not only on the quality of priate choice of both drug and dose.
care provided by health care institutions and 4) Physicians should be alert to atypical
physicians, but also on the control of health drug responses or unexpected side ef-
care costs. fects when they treat patients from varied
racial and ethnic backgrounds. Dosage
1) Health care institutions should monitor, adjustments should be made for patients
and restrict if necessary, the practice of from different racial and ethnic groups if
therapeutic substitution of drugs within pharmacological evidence supports the
the same drug classes. Patients in partic- adjustment.
ular racial and ethnic groups may be sub- 5) Finally, and perhaps most important, all
24 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
who are involved in patient care should 18. Vesell ES. The influence of host factors on drug re-
sponse. I. Ethnic background. Ration Drug Ther. 1979;13:1-7.
be aware of the growing clinical rele- 19. Lin K-M, Poland RE. Ethnicity, culture, and psychophar-
vance of pharmacogenetics in determin- macology. In: Bloom FF, Kupfer DJ, eds. Psychopharmacology. The
ing differences in patient responses to Fourth Generation of Progress. American College of Neuropsyco-
pharmacology, New York, NY: Raven Press, 2000;1907-1917.
drug therapy. 20. Weber WW. Populations and genetic polymorphisms.
Mol Diagn. 1999;4:299-307.
REFERENCES 21. Luzzatto L, Notaro R. Malaria. Protecting against bad
1. Institute of Medicine Report. Unequal treatment: con- air. Science. 2001;293:442-443.
fronting racial and ethnic disparities in healthcare. Washington, 22. Bech-Thomsen N, Angelo HR, Wulf HC. Skin pigmen-
DC. 2002. National Academy Press. tation as a predictor of minimal phototoxic dose after oral me-
2. Bach PB, Cramer LD, Warren JL, Begg CB. Racial dif- thoxsalen. Arch Dernatol. 1994;130:464-468.
ferences in the treatment of early-stage lung cancer. New Engl 23. Kligman AM, Kaidbey KH. Phototoxicity to benoxapro-
JMed. 1999;341:1198-1205. fen. EurJ Rheumatol Inflamm. 1982;5:124-137.
3. Bernabei R, Gambassi G, Lapane K, et al. Management 24. Tseng C, Hoffman B, Kurimoto I, et al. Analysis of
of pain in elderly patients with cancer. JAMA. 1998;279:1877- effects of ultraviolet B radiation on induction of primary allergic
1882. reactions. J Invest Dermatol. 1992;98:871-875.
4. Moore RI, Stanton D, Gopalan R, Chaisson RE. Racial 25. Kalow W. Pharmacoanthropology: outline, problems,
differences in the use of drug therapy for HIV disease in an and the nature of case histories. Fed Proc. 1984;43:2314-2318.
urban community. N Engl JMed. 1994;330:763-768. 26. Kleinman A, Eisenberg L, Good B. Culture, illness, and
5. Shapiro MF, Morton SC, McCaffrey DF, SenterfittJW, et care: clinical lessons from anthropologic and cross-cultural re-
al. Variations in the care of HIV infected adults in the United search. Ann Intern Med. 1978;88:251-258.
States: Results from the HIV Cost and Services Utilization Study. 27. Lawson WB. Clinical issues in the pharmacotherapy of
JAMA. 1999;281:2305-2375. African-Americans. Psychopharmacol Bull. 1996;32:275-281.
6. Schneider EC, et al. Racial differences in cardiac revas- 28. Kleyn PW, Vesell ES. Genetic variation as a guide to drug
cularization rates: does "overuse" explain higher rates among development. Science. 1998;281:1820-1821.
white patients? Ann Intern Med. 2001;135:328-337. 29. Evans WE, Relling MV. Pharmacogenomics: translating
7. Freeman HP, Payne R. Racial Injustice in health care. functional genomics into rational therapeutics. Science. 1999;286:
NEnglJ Med., 2000;342:1045-1047. 487-491.
30. Wolf CR, Smith G. Pharmacogenetics. BrMed Bull. 1999;
8. Morrison RS, Wallenstein S, et al: "We Don't Carry
55:366-386.
That"-Failure of pharmacies in predominately nonwhite neigh-
31. Siest G, Bertrand P, Herbeth B, et al. Apolipoprotein E
borhoods to stock opioid analgesics. N Engl J Med. 2000;342:
polymorphisms and concentration in chronic diseases and drug
1023-1026. responses. Clin Chem Lab Med. 2000;38:841-852.
9. Tai-Seale M, Freund D, LoSasso A. Racial disparities in
32. Linder MW, Prough RA, Valdes RJr. Pharmacogenetics:
service use among Medicaid beneficiaries after mandatory enroll- a laboratory tool for optimizing therapeutic efficiency. Clin Chem.
ment in managed care: indifference-in-differences approach. In- 1997;43:254-266.
quiry. 2001;38:49-59. 33. Zhou HH, Liu ZQ. Ethnic differences in drug metabo-
10. Fiscella K, Franks P, Gold MR, Clancy CM. Inequality in lism. Clin Chem Lab Med. 2000;38:899-903.
quality: addressing socioeconomic, racial, and ethnic disparities 34. Wood AJ, Zhou HH. Ethnic differences in drug dispo-
in health care. JAMA. 2000;283:2579-2584. sition and responsiveness. Clin Pharmacokinet. 1991;20:350-373.
11. Cavalli-Sforza LL. Genes, Peoples, and Languages. New 35. Comparison of propranolol and hydrochlorothiazide
York: North Point Press, 2000. for the initial treatment of hypertension. II. Results of long-term
12. Diamond J. Guns, Germs, and Steel. The Fates of Human therapy. Veterans Administration Cooperative Study Group on
Societies. New York: W. W. Norton & Co., 1999. Antihypertensive Agents. JAMA. 1982;248:2004-201 1.
13. Rana BK, Hewett-Emmett D,Jin L, et al. High polymor- 36. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser
phism at the human melanocortin 1 receptor locus. Genetics., response to angiotensin-converting-enzyme inhibitor therapy in
1999;151:1547-1557. black as compared with white patients with left ventricular dys-
14. Owens K, King MC. Genomic views of human history. function. NEnglJMed. 2001;344:1351-1357.
Science. 1999;286:451-453. 37. Lang CC, Stein CM, Brown RM, et al. Attenuation of
15. Schwartz RS: Racial profiling in medical research. NEngl isoproterenol-mediated vasodilatation in blacks. N Engl J Med.
J Med. 2001;344:1392-1393. 1995;333:155-160.
16. Poolsup N, Li Wan Po A, Knight TL. Pharmacogenetics 38. Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of
and psychopharmacotherapy. J Clin Pharn Ther. 2000;25:197- ethnic differences in drug disposition and response. Ann Rev
220. Pharmacol 7oxicol. 2001;41:815-850.
17. Meyer UA. Drugs in special patient groups: clinical im- 39. Comparison of propranolol and hydrochlorothiazide
portance of genetics in drug effects. In: Melmon KL, Morrelli for the initial treatment of hypertension. I. Results of short-term
HF, Hoffman BB, Nierenberg DW, eds. Melmon and Morrelli's titration with emphasis on racial differences in response. Veter-
Clinical Pharmacology: Basic Principles in Therapeutics, 3rd edition. ans Administration Cooperative Study Group on Antihyperten-
New York, NY: McGraw-Hill, Inc., 1992;875-894. sive agents. JAMA. 1982;248:1996-2003.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 25
ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS
40. Gibbs CR, Beevers DG, Lip GY. The management of 51. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascu-
hypertensive disease in black patients. QJM. 1999;92:187-192. lar morbidity and mortality in the Losartan Intervention For
41. Baker EH, Duggal A, Dong Y, Ireson NJ, Wood M, Endpoint reduction in hypertension study (LIFE): A randomized
Markandu ND, MacGregor GA. Amiloride, a specific drug for trial against atenolol. Lancet. 2002;359:995-1003.
hypertension in black people with T594M variant? Hypertension. 52. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular
2002;40:13-17. morbidity and mortality in patients with diabetes in the Losartan
42. Saunders E. Drug treatment considerations for the hy- Intervention For Endpoint reduction in hypertension study
pertensive black patient. J Fam Pract. 1988;26:659 - 664. (LIFE): A randomized trial against atenolol. Lancet. 2002;359:
43. Flack JM, Mensah GA, Ferrario CM. Using angiotensin 1004-1010.
converting enzyme inhibitors in African-American hypertensives: 53. Racial differences in response to low-dose captopril are
A new approach to treating hypertension and preventing target- abolished by the addition of hydrochorothiazide. BrJ Clin Phar-
organ damage. Curr Med Res Opin; 2000; 16:66-79. macol. 1982;14(suppl 2) :97S-1O1S.
44. Flack JM, Saunders E, Gradman A, et al. Antihyperten- 54. Chrysant SG, Brown RD, Kem DC, BrownJL. Antihyper-
sive efficacy and safety of losartan alone and in combination with tensive and metabolic effects of a new converting enzyme inhib-
hydrochlorothiazide in adult African Americans with mild to itor, enalapril. Clin Pharmacol Ther. 1983;33:741-746.
moderate hypertension. Clin Ther. 2001;23:1193-1208. 55. Goodman C, Rosendorff C, Coull A. Comparison of the
45. Prisant LM, Mensah GA. Use of beta-adrenergic recep- antihypertensive effect of enalapril and propranolol in black
tor blockers in blacks. J Clin Pharmacol. 1996;36:867-873. South Africans. S Aft Med J. 1985;67:672- 676.
46. Richardson AD, Piepho RW. Effect of race on hyperten- 56. Yancy CW, Fowler MB, Colucci WS, et al. Race and the
sion and antihypertensive therapy. IntJClin Pharmacol Ther. 2000; response to adrenergic blockade with carvedilol in patients with
38:75-79. chronic heart failure. NEnglJ Med. 2001;344:1358-1365.
47. Cushman WC, Reda DJ, Perry HM, Williams D, Abdel- 57. Strickland TL, Ranganath V, Lin KM, Poland RE, Men-
latif M, Materson BJ. The Department of Veterans Affairs Coop- doza R, Smith MW. Psychopharmacologic considerations in the
erative Study Group on Antihypertensive Agents. Regional and treatment of black American populations. Psychopharmacol Bull.
racial differences in response to antihypertensive medication use 1991;27:441-448.
in a randomized controlled trial of men with hypertension in the 58. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM,
United States. Arch Intern Med. 2000;160:825-831. Yunis EJ. HLA-B38, DR4, DQw3 and clozapine-induced agranu-
48. Saunders E, Weir MR, Kong W, et al. A comparison of locytosis in Jewish patients with schizophrenia. Arch Gen Psychia-
the efficacy and safety of a beta-blocker, a calcium channel try. 1990;47:945-948.
blocker, and a converting enzyme inhibitor in hypertensive 59. Turbay D, LiebermanJ, Alper CA, et al. Tumor necrosis
blacks. Arch Intern Med. 1990;150:1707-1713. factor constellation polymorphism and clozapine-induced agran-
49. Saunders E, Curry C, HindsJ, et al. Labetalol compared ulocytosis in two different ethnic groups. Blood. 1997;89:4167-
with propranolol in the treatment of black hypertensive patients. 4174.
J Clin Hypertens. 1987;3:294-302. 60. Meyer UA, Zanger UM. Molecular mechanisms of ge-
50. Townsend RR, DiPette DJ, Goodman R, et al. Combined netic polymorphisms of drug metabolism. Ann Rev Pharmacol
alpha/beta-blockade versus beta 1-selective blockade in essential Toxicol. 1997;37:269-296.
hypertension in black and white patients. Clin Pharmacol Ther. 61. Kalow W. Ethnic differences in drug metabolism. Clin
1990;48:665-675. Pharmacokinet., 1982;7:373-400.
26 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002