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RACIAL AND ETHNIC DIFFERENCES INRESPONSE TO MEDICINES: TOWARDSINDIVIDUALIZED PHARMACEUTICAL

TREATMENTValentine J. Burroughs, MD, Randall W. Maxey, MD, PhD, and Richard A. Levy, PhD

Washington, DC and Reston, Virginia

It is now well documented that substantial disparities exist in the quality and quantity ofmedical care received by minority Americans, especially those of African, Asian and Hispanicheritage. In addition, the special needs and responses to pharmaceutical treatment of thesegroups have been undervalued or ignored. This article reviews the genetic factors that underlievarying responses to medicines observed among different ethnic and racial groups. Pharmaco-genetic research in the past few decades has uncovered significant differences among racial andethnic groups in the metabolism, clinical effectiveness, and side-effect profiles of many clinicallyimportant drugs. These differences must be taken into account in the design of cost managementpolicies 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 l ethnicity lpharmaceuticals lpharmacogenomics

The recent report of the Institute of Medi-cine (IOM), “Unequal Treatment: ConfrontingRacial and Ethnic Disparities in Healthcare,”illustrates in eloquent scientific detail that ra-cial and ethnic disparities in health care doexist and are prevalent in both the treatment ofmedical illness and in the delivery of health

care services to minorities in the United States.1Of greater significance is the finding that thesedisparities still exist even after adjustment fordifferences in socioeconomic status, insurancecoverage, income, age, comorbid conditions,expression of symptoms, and access-related fac-tors. These disparities are not confined to anyone aspect of the health care setting, and caneven be found in the delivery of pharmaceuti-cal services, which are under increasing costcontrol measures.

Implicit in this transaction is the ultimateoutcome of increased morbidity and mortalityfor African Americans and other minorities.This is mostly due to a diminished quality ofmedical care and health services, but also dueto a predilection to avoid using better quality

© 2002. From the Health Policy Committee, Board of Trustees, Na-tional Medical Association, Washington, DC; and Scientific Affairs,National Pharmaceutical Council, Reston, Virginia. Requests for re-prints should be addressed to Dr Richard Levy, National Pharmaceu-tical Council, 1894 Preston White Drive, Reston, VA 20191.

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002 1

but higher costing pharmaceuticals in the treat-ment of African American and other minoritiesby practitioners and health care institutions.

The conscious or unconscious decision byhealth care providers to withhold needed phar-maceuticals and services from minorities ismost notable in several key diseases. Studies incancer patients demonstrate that chemothera-py2 and analgesic therapy3 are more likely to begiven to nonminorities. African Americans withHIV disease are less likely to receive antiretro-viral agents,4 prophylaxis for Pneumocystis pneu-monia and protease inhibitors compared withnonminorities.5 In the area of cardiovascularcare, there are clear differences in treatmentregimens after coronary angiography, not re-lated to clinical factors.6 As reported elsewherein this publication, studies have shown that Af-rican Americans and Hispanics receive fewerantidepressants for clinical depression, and arerelatively under-treated with analgesics for painfrom fractures or postoperative pain.7 AfricanAmerican and Hispanic patients with severepain of any cause are less likely than Whitepatients to be able to obtain commonly pre-scribed pain medicine because pharmacies inpredominately non-White communities do notnormally carry adequate stocks of opiates.8

In assessing potential sources of disparitiesin health care, the 2002 IOM report identifiedpatient-level, provider-level and health care sys-tem-level factors that might play a role beyondaccess-related causes of disparities. Patient-leveland provider-level attributes were felt to belargely based on racial attitudes, discrimina-tion, bias, stereotypes, and clinical uncertain-ties that exist in the United States. This is re-flected in their conclusion “that much ofAmerican social and economic life remains or-dered by race and ethnicity, with minoritiesdisadvantaged relative to Whites.”

Health care system-level factors, however,can be influenced and modified by govern-ment through appropriate public policy. Thecurrent evolution in the organization, financ-ing and delivery of health care services, includ-ing pharmaceutical services, toward managed

care models bent on cost containment has ad-versely affected African Americans and minor-ities.9

Publicly funded managed care plans, espe-cially Medicaid HMOs, may paradoxically re-duce access to health care services for minori-ties.9 A distressing outgrowth of these efforts tocontain costs in public insurance plans is theemergence of new state laws requiring genericdrug substitutions for Medicaid recipients. Ef-fective October 1, 2002, in New York and otherstates, Medicaid patients will have to use ge-neric drugs in lieu of brand name drugs as amatter of law, if such drugs have been deter-mined to be “therapeutically equivalent.” Ex-emptions can be sought by persons or entitiesproviding a valid study showing that the ge-neric is less effective than the brand, has unto-ward outcomes or adverse side effects, or apotential negative impact on a recipient withina special population. This will impose barriersthat busy health care providers can seldomovercome. It also imposes an additional dutyand obligation upon health care institutionsthat serve these patients to monitor outcomesin using generic drugs on “all comers.”

There is good evidence to show that thera-peutic substitution of drugs within the sameclass places minority patients at greater risk.This is because effectiveness and toxicity canvary among racial and ethnic groups. Physi-cians and managed care plans must be morealert under these new “formulary laws” for atyp-ical drug responses or unexpected untowardside effects when treating patients from racialand ethnic minority groups. Dosage adjust-ments might be necessary in using genericdrugs as therapeutic substitutions in untestedracial and ethnic groups. There is a distinctpossibility of a toxic accumulation of suchdrugs from slower metabolism, or the need formedical service substitutions to supplement theineffective generic drugs in some racial andethnic and minority groups. Either outcomewill demand a greater use of health systemresources and thus obviate the original pur-pose of cost containment.

ETHNIC AND RACIAL DIFFERENCES IN PHARMACEUTICALS

2 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 94, NO. 10 (SUPPL), OCTOBER 2002

The high concentration of minorities withinthe Medicaid population and with “bare bones”health plans sets the stage for health care dis-parities in the statutory use of “therapeuticallyequivalent,” but untested, generic drugs withinthis group. This typifies what is referred to inthe 2002 IOM report as the socioeconomicfragmentation of health plans. It has been sug-gested that such fragmentation leads to thedevelopment of “different clinical cultures,with different practice norms, tied to varyingper capita resource constraints.” None of thisfavorably impacts outcomes in health care forracial and ethnic minorities.

A greater effort must be undertaken by pol-icy makers to hold publicly funded health plansaccountable for providing beneficiaries withproducts and services equal in quality to thoseof privately funded health plans.10

Consideration must also be given for patientprotections as more beneficiaries are enrolledin Medicaid managed care HMOs. As with pri-vate managed care organizations, a number ofissues should be addressed, including full phar-macy benefits. A clear mechanism must be inplace to appeal denied services and the avail-ability of nonformulary medications. The latterbecomes particularly important in assessing theprovision of needed brand name, nongenericmedications in states where the statutory use of“therapeutically equivalent” generic drugs ismandated. The physician’s duty is to prescribethe most efficacious and safe drug for patientseven if a lengthy appeals process before aformulary committee or institutional board isthe price to pay to best serve the patient’sinterest.

The goal of individualized pharmaceuticaltherapy is to provide the right drug to the rightpatient for the right illness in the right dose atthe right time. The recent confirmation of thelarge gaps in health care equality between mi-norities and whites in America should providea further incentive and a redoubling of theefforts of all responsible health care providersto rapidly close this gap.

EXECUTIVE SUMMARYThis monograph reviews the genetic, envi-

ronmental, and cultural factors that underlievariations in drug response among differentracial and ethnic groups. (While the meaningsof the terms ‘racial’ and ‘ethnic’ continue toevolve, here ‘racial’ refers to genetically de-fined differences—most obviously, for exam-ple, skin pigmentation—while ‘ethnic’ refers tocultural differences. Thus, ‘Hispanic’ definesan ethnic group that includes several differentraces.) Racial and ethnic groups comprise im-portant subpopulations whose special needsand drug responses have traditionally been un-dervalued or ignored. The article focuses ondrug classes in which differences in drug re-sponse because of racial and ethnic variationmay directly affect institutional policies such asformulary management, therapeutic drug sub-stitution, and step-care protocols. Available in-formation suggests that patients in particularracial and ethnic groups may be subject togreater risks than those in other groups if theyare prescribed or switched to an “equivalent”drug because: (1) the agent may not be aseffective; or (2) substantial dosage adjustmentsmay be necessary to avoid overdosing or under-dosing.

The factors determining racial variations inresponse to medications are complex and in-terdependent. Environmental factors (climate,smoking, alcohol consumption, etc.) may havea profound effect on drug metabolism and dis-position. Cultural or psychosocial factors mayaffect the efficacy of or adherence to a partic-ular drug therapy. Genetic factors, however,are the major determinants of the normal vari-ability in drug effects. The study of geneticallydetermined variations in drug response result-ing from inherited differences in drug metab-olism or drug targets is called pharmacogenet-ics, when referring to the study of individualgenes, or pharmacogenomics, when referringto the study of all of the genes, i.e., genome.

Pharmacogenetic research in the past fewdecades has uncovered significant differences



among racial and ethnic groups in the metab-olism, clinical effectiveness, and side effect pro-files of therapeutically important drugs. Moststudies have concentrated on cardiovascularagents (beta-blockers, diuretics, calcium chan-nel blockers, and angiotensin-converting-en-zyme inhibitors) or central nervous systemagents (antidepressants and antipsychotics).Analgesics (acetaminophen, codeine), antihis-tamines, and alcohol are other pharmacologiccompounds with varying effects among differ-ent racial and ethnic populations. Most of theresearch applies to African Americans, Asians,and Whites. Fewer studies have specifically tar-geted Hispanics who, according to the 2000 USCensus, are now the largest racial or ethnicgroup after Whites.

Genetic PolymorphismsPolymorphisms are naturally occurring vari-

ants in the structures of genes and the productsthey encode. The relevant gene products hereare drug metabolism enzymes, receptor pro-teins, and other proteins involved in drug re-sponse or disease progression. Polymorphismsoccur in all human genes, but only some ofthem alter the functioning of the gene prod-uct, and only some of these vary significantly infrequency among different populations. Poly-morphisms in drug metabolism enzymes havebeen intensively studied because they affectmany drugs across different drug classes. Thetwo most important polymorphisms for thisdiscussion affect the metabolism of antiarrhyth-mics, antidepressants, beta-blockers, neuro-leptics, opioids, barbiturates, and benzodiaz-epines. A third polymorphism affectsmetabolism of caffeine and isoniazid. This poly-morphism was first studied when isoniazid wasintroduced for the treatment of tuberculosis.Patients were classified as fast or slow elimina-tors of isoniazid on the basis of a geneticallydetermined defect in their ability to metabolizethe drug. The proportions of rapid acetylatorsand slow acetylators vary considerably in differ-ent populations: 52 to 62% of Whites are slow

acetylators compared to 7 to 34% of Chineseand Japanese.

Polymorphisms in drug targets and proteinsinvolved in disease progression can be majordeterminants of drug efficacy. Polymorphismsin the gene encoding the serotonin receptoralter response to clozapine and antipsychotics.Polymorphisms in apolipoprotein E (Apo E), aprotein involved in cholesterol homeostasis, al-ter the risk of developing Alzheimer’s diseaseand the response to tacrine treatment. Tacrineis less effective in individuals carrying a partic-ular Apo E polymorphism that is more preva-lent in African Americans and Africans (20% to30%) than among Asian populations (5% to10%).

ImplicationsPolymorphisms may influence a drug’s ac-

tion by altering its pharmacokinetic (absorp-tion, distribution, metabolism, excretion) orpharmacodynamic (effect on the body) prop-erties. Clinically, there may be an increase ordecrease in the intensity and duration of theexpected drug effect and substantial dosageadjustments may be necessary for individualsfrom different populations. Importantly, be-cause different agents of the same drug classare often cleared by different metabolic path-ways, drugs of a class may differ in their suscep-tibility to genetic differences in metabolism. Inaddition, the pathophysiology of disease maydiffer among racial groups (e.g., hypertension)and some agents will be more effective thanothers in a given racial group.

RecommendationsAttention should be paid to the need to in-

dividualize drug therapy for specific popula-tion groups by health care policy makers andproviders. The following recommendationscan have positive benefits on the quality of carefor racial and ethnic subpopulations and mayalso help to control health care costs.

1) Health care institutions should limitthe practice of therapeutic substitution,



i.e., the interchange of agents of thesame pharmacologic or therapeutic class.Patients of certain racial and ethnicgroups are subject to greater risks if theyare prescribed an “equivalent” drug. Insome cases, substantial downward dosageadjustments may be necessary, since indi-viduals in these groups may not be able totolerate standard dosage levels. Alterna-tively, standard doses of some agents of aclass may not be effective in certain racialand ethnic groups. Other cost manage-ment programs that restrict access topharmaceuticals, such as formularies,step-care protocols, and tiered copay-ments, should be broad and flexibleenough to enable rational choices ofdrugs and dosages for all patients, re-gardless of race or ethnic origin.

2) Physicians should give individualizedtreatment to each patient and resist thetemptation to apply “cook-book” drugtherapy that does not take into accountracial or ethnic origin. Physicians shouldalso be alert to atypical drug responses orunexpected side effects (especially withcardiovascular or psychotropic agents)when they treat patients from diverse ra-cial and ethnic backgrounds. Dosage ad-justments may be required in some pa-tients, if supported by pharmacologicalevidence.

3) Pharmaceutical companies should con-tinue to include significant numbers ofpatients representing varied racial andethnic groups in drug metabolism studiesand clinical trials. Most companies testand evaluate new pharmacological com-pounds on numerous population sub-groups. Inclusion of different racial andethnic populations in clinical trials islikely to reveal drug actions and side ef-fects specific to these groups, and mayalso to lead to the discovery of therapiesof specific advantage to patients of variedracial and ethnic backgrounds.

Toward Individualized TherapyRace or ethnicity is a risk factor that

changes the probability that an individualwill respond in the expected way to a givendrug therapy. However, “race” is an impre-cise label for genetic variations that an indi-vidual person might or might not possess.Technological advances in the wake of theHuman Genome Project will eventually en-able us to move beyond race and to tailordrug therapy precisely to each patient. It isnow possible to take a genetic ‘fingerprint’ ofan individual and determine precisely thepresence of polymorphisms in the genesknown to be involved in drug interaction.Instead of a person’s race or ethnicity beinga risk factor for the possession of polymor-phisms involved in drug response, a geno-typic profile can determine with certaintywhether or not the individual possesses thesepolymorphisms.

In the future, drug treatment will be indi-vidually tailored rather than race-based. Ge-netic fingerprinting using DNA arrays is al-ready practical, but the knowledge baserelating genomic variations to drug responseand disease progression has not been devel-oped. Studies in which DNA fingerprints arecorrelated with data present in medicalrecords about medical history and drug re-sponse will have a profound impact on theways in which new drugs are developed andused.

INTRODUCTIONCost Control and Restricted Access toPharmaceuticals

Many polices aimed at managing the cost ofmedications—including restrictive formularies,substitution of alternative drugs of a class, man-dating the use of specific agents, step-care pro-tocols specifying the order in which agents areused, tiered copayments, and prior authoriza-tion for certain drugs—have been introducedwith little consideration of any possibly discrim-inatory effects on racial and ethnic groups.



Prior authorization by Medicaid programs iswidespread. Prior authorization is sometimesused to limit access to newer generation phar-maceuticals and represents an administrativeburden on physicians and their staff who mustobtain clearance from Medicaid before pre-scribing certain medications. In addition, forcertain subpopulations that have a differentresponse to medication or who have differentsymptoms, such limitations may produce sub-optimal, adverse, or unexpected responses.Health care plans have turned to formularies inan attempt to manage their drug costs but of-ten with unintended consequences. Studiesshow that restrictive formularies can result inservice substitution—that is, the replacementof medications with medical services at a muchhigher cost. Because of the strong associationwith increased use of health care services, thepolicy of restricting formularies should be re-examined. The practice of tiered copay-ments—i.e., the policy of escalating copay-ments for nonformulary drugs of substitutionof brand name for generic drugs—is formularyrestriction in another guise.

Disease management is an alternative strat-egy to prior authorization and other policiesthat limit access to pharmaceuticals, which en-sures access to state-of-the-art pharmaceuticalswhile controlling overall costs. Disease manage-ment benefits chronically ill patients, ensuresmore appropriate use of medications, and low-ers unnecessary spending.

Effects of Restrictive Policies on Patients fromVaried Racial and Ethnic Backgrounds†

Disparities in the quality of medical care pro-vided to patients of different racial and ethnicgroups have been extensively documented.10

Most studies have focused on African Ameri-cans, but other studies have shown that His-panic and Asian Americans are similarly af-

fected. Patients in these groups receive lessintensive medical treatment than the nation asa whole, including fewer vaccinations, less drugtherapy for pain, fewer antiretroviral drugs forHIV/AIDS, and fewer antidepressants. AfricanAmerican and Hispanic patients with severepain are less likely than White patients to beable to obtain commonly prescribed pain med-icines, because pharmacies in predominantlynon-White communities do not carry adequatestocks of opiates. Other studies have revealedunder-treatment of Hispanics and AfricanAmericans for pain from fractures, inadequatemanagement of postoperative pain in non-White patients, and a lower likelihood of cura-tive surgery for cancer in African Americansthan in Whites of equivalent socioeconomicstatus.7

The demographic changes anticipated overthe next decade magnify the importance ofthese disparities. According to the 2000 census,racial groups other than ‘White’ make up 33%of the U.S. population (Fig. 1).‡ African Amer-icans and Hispanics represent a growing per-centage of the urban population in the UnitedStates. These groups constitute the new urbanmajority in American cities such as Washing-ton, Detroit, and Los Angeles. Moreover, a dis-proportionate percentage of these Americansin urban areas depend on Medicare and Med-icaid as their sole health care providers. Con-sequently, these programs should not adoptpolicies that ignore the special needs of a grow-ing percentage of the patient groups they areintended to serve. Inappropriate policies re-garding the impact of race and ethnicity onpharmaceuticals can have wide-ranging and po-tentially damaging implications.

†While the meanings of the terms ‘racial’ and ‘ethnic’ continue toevolve, here ‘racial’ refers to genetically defined differences, while‘ethnic’ refers to cultural differences. Thus, ‘Hispanic’ defines an ethnicgroup that includes several different races.

‡The classifications of race and ethnicity were different in the 2000census than in earlier censuses. In 2000, almost seven million individ-uals reported belonging to two or more racial categories. Ethnic originwas considered to be a separate concept from race, so that people ofHispanic origin could belong to any racial category. Hispanics madeup 12.5% of the total 2000 population. Of the 87.5% that were notHispanic, 79.0% were White.



Purpose of this ReportThis report has several purposes: (1) to re-

view the interrelated causes of variability in re-sponse to medicines among racial and ethnicgroups (focusing on the pharmacogenetics ofdrug metabolism as the factor most intensivelyresearched); (2) to discuss the genetic poly-morphisms known to be relevant to the effectsof drugs; (3) to discuss the variation of thesepolymorphisms among different racial groups;(4) to discuss examples of drugs to which racialand ethnic groups respond differently; (5) todiscuss the implication for formulary decisionsand other institutional policies such as thera-peutic substitution and step-care protocols; and(6) to make recommendations for health careproviders and policy makers who are responsi-ble for clinical decisions affecting patient care.

ORIGINS OF GENETIC DIFFERENCES AMONGPEOPLESHuman Migration

The ‘Out of Africa’ theory of human evolu-tion is based on the distribution of geneticpolymorphisms,§ the archeological record, and(for the most recent events) linguistics. In bareoutline, it reads as follows:

Anatomically modern humans evolved in Af-rica by about 100,000 years ago.11 Some ofthese people migrated from East Africa intoEurasia and subpopulations spread east intosouthern Asia. Australia was inhabited around50,000 years ago (and subsequently remainedcompletely isolated from the rest of the worlduntil the late 18th century). Modern humansfirst inhabited Western Europe by about 40,000years ago. The northern latitudes were pene-trated quite late. After the inhabitation of Sibe-ria 15,000 to 35,000 years ago, humans spilledinto Alaska and rapidly occupied the whole ofthe North and South American continents.The Pacific islands were colonized by peoplesoriginating in South China beginning about5,500 years ago and continuing into the his-toric period.12

Two factors led to genetic differences amongpeoples and hence potential differences indrug response. First, genetic mutations contin-ued to arise spontaneously in populations thatwere geographically isolated form one another.These mutations were subject to environmentalselection. Second, because these populationmovements were initiated by subgroups of peo-ple, they tended to represent only a particularsubset of the genetic polymorphisms that werepresent in the entire human population. Thesmaller the migrant subgroup, the more genet-ically distinct it would be from other sub-groups—a phenomenon called the ‘foundereffect’—leading to distinct patterns of poly-morphisms in the descendent populations. Hu-man populations continued to migratethroughout prehistoric and historic times, dis-placing, coexisting, or intermixing with indig-enous peoples. The result is that there are nodistinct geographic boundaries between ge-netic variations; rather, there are gradations inthe prevalence of polymorphisms across geo-graphical distance.

Environmental SelectionStereotypic features of the different ‘races,’

skin color in particular, but also hair color andtexture, body shape, and facial details, are su-

§Polymorphisms are naturally occurring variants in the structures ofgenes and the products they encode.

Figure 1. Racial composition of the US population. Source:Bureau of Census data for 2000.



perficial and are thought to be adaptations toclimate and geography involving relatively fewgenetic changes. The loss of skin pigmentationamong peoples living at high latitudes (the‘White race’) is hypothesized to have been se-lected for by the requirement for exposure tosunlight for the biosynthesis of vitamin D andhence the prevention of rickets. Skin color isdetermined by melanins whose production ishormonally regulated via the MC1R (melano-cortin-stimulating hormone receptor) gene.Multiple polymorphisms in MC1R that haveevolved relatively recently may explain much ofthe variation in skin color.13

Genetic Variation within and betweenPopulations

Most human genetic variation antedates themigration of modern humans out of Africa. Putdifferently, most genetic variation occurs withinany given population rather than between popu-lations. An average population from anywhere inthe world includes 85% of all the variation inautosomal genes (genes on chromosomes otherthan the sex chromosomes). Differences amongpopulations from the same continent contribute6% of genetic variation, and differences amongpopulations from different continents contribute9% to 13%.14

The Uses of Racial Categorization in MedicineIndividual genetic polymorphisms change

gradually in prevalence across continents anddo not separate populations into clearly de-marcated groups that correspond to the pop-ular idea of race. Physical traits commonlyassociated with ‘racial’ groups—skin and haircolor, facial features, etc.—are superficialcharacteristics that have little relevance tothe response to drugs or to the progressionof complex diseases such as diabetes mellitus,coronary heart disease, and so forth.14,15

What, then, is the scientific rationale for racecontinuing to occupy such an importantplace in the medical consciousness? Geneti-cally determined differences in the responseto drugs do exist among individuals, and

there are differences in the prevalence ofthese determinants among different popula-tions. Research in the last 35 years has uncov-ered significant differences among racial andethnic groups in their rates of drug metabo-lism, in clinical responses to drugs, and indrug side effects. African American andWhite patients differ significantly in their re-sponses to beta-blockers, ACE inhibitors, anddiuretics used either alone or in combinationfor the treatment of hypertension. Chineseare considerably more sensitive than Whitesto the effects of the beta-blocker propranololon heart rate and blood pressure. Asians aremore likely to require lower dosages thanWhites of a variety of different psychotropicdrugs, including lithium, antidepressants,and antipsychotics.

Race is an imprecise substitute measure ofthese genetic differences. When relevant to aparticular drug, race and ethnicity should beconsidered along with other factors such asage, gender, diet, smoking status, and otherfactors that modify, often only slightly, therisk of disease or drug response. Practicingphysicians treating individual patients and,equally importantly, institutional policy mak-ers should be sensitive to the implications ofracial and ethnic differences in drug therapy.Restrictive policies may pose greater degreesof risk for patients of different racial andethnic backgrounds. A clear message of therecent findings in this field is that racial andethnic differences must be factored into for-mulary selection and prescribing decisionson an individual basis. Otherwise, thesegroups may be disadvantaged by institutionalpharmaceutical policies that restrict individ-ualized drug therapy.

INTERPLAY OF GENETIC, ENVIRONMENTAL,AND CULTURAL FACTORS

The factors contributing to variability indrug response are complex and interrelated(Fig. 2). Differences in drug response amongracial and ethnic groups are determined by



genetic, environmental, and cultural (mean-ing, in this context, psychosocial) factors.These factors may operate independently ofone another, or they may interact dynamicallyand synergistically.

Biological FactorsAge and sex, of course, affect drug response,

but the primary biological factor we are con-cerned with is genetics. Studies of twins andblood relatives have shown that genetic factorsare the major biological determinants of thenormal variability of drug effects and are re-sponsible for many differences in pharmaco-logic activity among normal subjects studiedunder carefully controlled environmental con-ditions. Over 100 examples have been docu-

mented in which inherited individual traitswere implicated in atypical, exaggerated re-sponses to drugs, novel drug effects, or lack ofeffectiveness of drugs.17

The genetic makeup of an individual maychange the action of a drug in a number ofways as it moves through the body. Geneticfactors may influence a drug’s action by alter-ing its pharmacokinetic properties (absorp-tion, distribution, metabolism, excretion) orpharmacodynamic properties (effect on thebody). Clinically, there may be an increase ordecrease in the intensity and duration of theexpected typical effect of the drug.

The study of genetically determined varia-tions in drug response is called pharmacoge-netics. Variations in drug response are caused

Figure 2. Factors contributing to variability in drug response. Adapted from Poolsup et al. (2000).16



by gene polymorphisms. Genes are consideredto be functionally polymorphic when variantsof the gene exist stable in the population, oneor more of which alters the activity of the geneproduct (which is typically a protein such as adrug metabolizing enzyme or a drug receptor).Pharmacogenetics has traditionally meant thestudy of polymorphisms in individual genes.This field has now broadened into pharmacog-enomics, which examines the effects of the en-tire genome, i.e., all of the genes, on drugresponse. In pharmacogenomics, large arraysof genes are studied in parallel, so that theentire spectrum of genes that determine theresponse to a particular drug can be examinedat one time.

Environmental FactorsEnvironmental factors—diet, climate, smok-

ing, alcohol, drugs, pollutants16—may causewide variations in drug response within an in-dividual and even wider variations betweengroups of individuals. Several of these factorscan operate simultaneously in the same indi-vidual, thus affecting the processes of drug ab-sorption, distribution, biotransformation, ex-cretion, and receptor interaction in differentways and to different degrees.18

Differences in diet may significantly alter themetabolism rate or drug blood levels amongdifferent ethnic populations. Studies compar-ing the metabolism of antipyrine betweenAsian Indians in rural Indian villages and In-dian immigrants in England demonstrated thatas immigrants adopted the lifestyle and dietaryhabits of the British, their drug metabolismaccelerated. Similar findings have been ob-served among Sudanese and Western Afri-cans.19

A striking example of the interplay of envi-ronmental and genetic factors is found in therelationship between malaria and expression ofthe gene G6PD in red blood cells. G6PD en-codes an enzyme (glucose-6-phospate dehydro-genase), a deficiency of which leads to anemiaif the person is exposed to certain foods (e.g.,fava beans) or drugs (e.g., primaquine).20 Evi-

dence has accumulated that a G6PD deficiencyprotects against infection with P. falciparum, theparasite that causes a fatal form of malaria.Variants in G6PD that lead to reduced enzymeactivity occur much more frequently in coun-tries in which malaria is or was endemic (seeFig. 3). There are more than 30 polymorphismsthat result in G6PD deficiency and hence pro-tection against P. falciparum. These polymor-phic variants, and the ancestral strain of P.falciparum, arose between about 3,000 and10,000 years ago, coincident it is believed withthe spread of farming, which provided condi-tions conducive to the spread of malaria.21

Skin pigmentation is also the result of aninteraction between genetic and environmen-tal factors. Light-skinned individuals are sub-ject to drug-induced phototoxicity after ingest-ing certain drugs.22–24

Cultural FactorsCultural or psychosocial factors, such as the

attitudes and beliefs of an ethnic group, mayaffect the effectiveness of, or adherence to, aparticular drug therapy. Cross-disciplinaryfields—pharmacoanthropology, medical an-thropology, and cultural psychiatry—haveemerged to study these issues. Pharmacoan-thropology studies interethnic differences indrug responses by examining population char-acteristics in social and genetic terms and usingmethods suitable for pharmacological investi-gation of large numbers of subjects.25 Medicalanthropologists study the effects of a patient’sperception of illness and disease in a cross-cultural context to determine the role that eth-nic and cultural perceptions and beliefs play inthe patient’s adherence to or understanding ofmedical therapy or drug treatment. For exam-ple, the physician’s ability to treat a patienteffectively may be impeded by the patient’sculturally determined perception of the mean-ing of his or her illness.26 Cultural psychiatryfocuses on the interaction of culture and psy-chiatric disorders, and includes cross-culturaldifferences in symptoms and diagnoses, and



variations in dose response to psychotropicsamong different ethnic groups.

Studies have consistently shown that Afri-can-American patients are more likely to beoverdiagnosed as having a psychotic illnessand are more likely to be treated with neuro-leptics regardless of diagnosis.19,27 AfricanAmericans are also more likely to be placedon implanted or periodically injected ratherthan oral medications, reflecting physicians’concern about adherence. There is also evi-dence from large-scale drug trials that theplacebo response is greater among non-Whites. Other studies have shown that theperception and report of adverse effects ofdrugs are influenced by patients’ culturallydetermined beliefs.19

Investigators who study the effects of culturalor psychosocial factors on differing drug re-

sponses agree that these effects are real andcan be documented through case studies orepidemiological surveys. However, it is difficultto design large, controlled clinical trials to iso-late any of these factors and determine its ef-fect as an independent variable on drug re-sponse in a particular ethnic group. Thecomplex interrelationships of environmentaland cultural factors make them less readilyamenable to reproducible results, so that re-search in this field so far has concentrated onidentifying genetic factors.

GENETIC POLYMORPHISMS IN DRUGMETABOLISM, DRUG TARGETS, AND DISEASEPATHWAYSOverviewPolymorphisms are naturally occurring variantsin the structures of genes and the products they

Figure 3. Interplay of environmental and genetic factors: the global distribution of G6PD deficiency. The colored areas inthe map indicate the prevalence of the G6PD deficiency. A deficiency in G6PD appears to protect against infection witha parasite (P. falciparum) that causes a fatal form of malaria. The countries in which G6PD deficiency is most commoncorrespond to those in which malaria is (or was) endemic (regions endemic for malaria not indicated on map). Adaptedfrom Luzzatto & Notaro (2001).21



encode. The gene products are usually pro-teins that interact in some way with drugs. Poly-morphisms affecting the response to drugs canoccur in genes involved in one of three pro-cesses or mechanisms—drug metabolism, drugtargets, and the disease pathway. An exampleof each of these three mechanisms is shown inTable 1. Of the three mechanisms, polymor-phisms in drug metabolism genes are consid-ered most important because they act acrossclasses of drugs, whereas a mutation in thegene encoding a drug target (such as a recep-tor protein) will only affect the class of drugsthat interacts with that target.

Although there are polymorphisms in allgenes controlling drug effects, they do not nec-essarily alter drug response and do not neces-sarily show significant variation among popula-tions. In this discussion, we shall focus on thosepolymorphisms known to have clinically impor-tant roles and to vary among populations.

Polymorphisms of Drug MetabolismMost drugs are chemically modified (bio-

transformed) and thus inactivated in the liver

before their clearance from the bloodstreamand elimination from the body. Biotransforma-tion is most commonly a process of oxidationor of acetylation or methylation (Table 2).Most oxidation is performed by one of severaloxidative enzyme systems associated with cyto-chrome P450. These enzymes are now referredto by their genetic names (CYP2C9, CYP2C19,CYP2D6, etc.), although they were originallyreferred to by the test drugs (or ‘probe’ drugs)whose metabolism they controlled: debriso-quine or sparteine for CYP2D6, mephenytoinfor CYP2C19, and phenytoin for CYP2C9.Other important drug metabolism genes arethe acetylation gene NAT2 (encoding N-acetyl-transferase 2) and the methylation gene TPMT(encoding thiopurine methyltransferase).

Common polymorphisms in drug metabo-lism genes have received the most attentionbecause they affect the metabolism of manyclinical important drugs and large numbers ofpatients. Polymorphic variants in these genesalter the activity of the encoded enzyme mostoften by reducing it, sometimes by eliminating

Table 2. Polymorphic Genes Influencing Drug Metabolism

Mechanism Enzyme Gene Common probe drugs

Oxidation Cytochrome P450 enzymes CYP2C9 Warfarin, phenytoinCYP2C19 MephenytoinCYP2D6 Debrisoquine, sparteine, dextromethorphan

Alcohol dehydrogenase ADH3 EthanolAcetylation N-Acetyltransferase 2 NAT2 Caffeine, sulphamethazine, isoniazidMethylation Thiopurine methyltransferase TPMT Mercaptopurine, thioguanine, azathioprine

Source: Poolsup et al. (2000),16 Evans & Relling (1999).29

Table 1. Mechanisms and Examples of Clinically Relevant Genetic Polymorphisms Influencing Drug Metabolism andEffects

Mechanism Example Pharmacogenetic effect

Drug metabolism Cytochrome P450 EnzymeCYP2D6

“Poor metabolizer” phenotype in ;25% of all drugs

Drug target Serotonin (5-HT2A) receptor Altered binding of the atypical antipsychoticclozapine

Disease pathway Cholesterol esterase transportprotein (CETP)

Atherosclerosis progression and response to theHMG-CoA inhibitor pravastatin

Source: Kleyn & Vesell (1998).29



it, and occasionally by enhancing it. This leadsto differential rates of metabolic clearance ofthe drug metabolized. Those individuals whodo not metabolize a certain drug efficiently arecalled “poor metabolizers” (PM), as opposed tonormal or “extensive metabolizers” (EM).

The effect of the poor metabolizer pheno-type is to increase the exposure to the activedrug by increasing the peak concentration inthe blood and the time to clearance. This is theequivalent of an overdose of the drug. Theefficacy is not enhanced because dosages arenormally targeted to have optimum efficacy,i.e., further increasing the dose does not fur-ther increase the effect. Adverse effects are in-creased, however, because dosages are nor-mally targeted to be close to the bottom of thethreshold where adverse effects begin to ap-pear. In sum, the poor metabolizer phenotypeeffectively decreases the therapeutic ratio (effi-cacy:toxicity) of the drug.29

Polymorphisms in CYP2D6 are among theclinically most important because so manydrugs are metabolized by this pathway, includ-ing antiarrhythmic, antidepressant, beta-blocker, neuroleptic, and opioid agents (Table3). The implications of the CYP2D6 poor me-

tabolizer phenotype are listed in Table 4. Dif-ferences in the frequency of the CYP2D6 poormetabolizer phenotype have been demon-strated among different racial and ethnicgroups and among subpopulations of the sameracial group.

Polymorphisms in CYP2C19 affect the me-tabolism of mephenytoin, hexobarbital, diaze-pam, omeprazol, and many other drugs (Table5). Some drugs, e.g., amitriptyline, clomipra-mine, propranolol, can be substrates for bothCYP2C19 and CYP2D6, indicating that there isredundancy and overlap between these two sys-tems.

Polymorphisms in NAT2, the gene encodingN-acetyltransferase 2, affect metabolism of caf-feine and other drugs, including isoniazid (Ta-ble 2). NAT2 polymorphisms were first studiedwhen isoniazid therapy was introduced for thetreatment of tuberculosis. Patients were classi-fied as fast or slow eliminators of isoniazid onthe basis of a metabolic defect in their ability tometabolize the drug. This polymorphism is es-pecially important in the study of racial andethnic drug responses because the proportionsof rapid acetylators (RA) and slow acetylators(SA) vary considerably in different ethnicand/or geographic populations.17

Polymorphisms of Drug TargetsDrug targets include hormone or neuro-

transmitter receptors, specific enzymes, andion channels (Table 6). Many of the genesencoding drug targets exhibit polymorphismsthat alter their sensitivity to particular medica-tions. Examples include: polymorphisms inbeta-adrenergic receptors and their sensitivityto beta-agonists in asthmatics; angiotensin-con-verting enzyme (ACE) and its sensitivity to ACEinhibitors; angiotensin II T1 receptor and vas-cular reactivity to phenylephrine or response toACE inhibitors; sufonylurea receptor and re-sponsiveness to sufonylurea hypoglycemicagents; and 5-hydroxytryptamine receptor andresponse to antipsychotics such as clozapine.29

The effect of a drug receptor mutant thatreduces binding of the target drug is to reduce

Table 3. Drugs Metabolized by CYP2D6

Drug class Drugs

PsychotropicAntipsychotics Haloperidol, perphenazine,

thioridazine, fluphenazine,clozapine, risperidone,chlorpromazine

Antidepressants Amitriptyline, clomipramine,desipramine, fluoxetine,imipramine, maprotiline,nortriptyline, paroxetine

CardiovascularAnti-arrhythmics Propafenone, flecainide,

sparteine, quinidineBeta-blockers Propranolol, timolol,

metoprolol, labetalolAntihypertensives Debrisoquine, clonidine

Miscellaneous Codeine, nicotine,methoxyamphetamine

Source: Poolsup et al. (2000).16



the efficacy of the drug and, hence, the thera-peutic ratio. Unlike the poor metabolizer phe-notype of drug metabolizing genes, there is nodirect effect on the incidence of adverse ef-fects.

Polymorphisms of Disease PathwaysGenetic polymorphisms that underlie dis-

ease pathogenesis can be major determinantsof drug efficacy (Table 7).

Apolipoprotein E is an example of proteinthat affects disease progression and the actionof drugs, and that exists in several polymorphicvariants. Apolipoprotein E is a circulating andtissue protein involved in cholesterol ho-moeostasis and other functions. Common ge-netic polymorphisms affect both the lipid andreceptor associations of apolipoprotein E, al-tering lipid profiles and correlating with dis-eases linked to lipid metabolism—particularlycardiovascular disease, but also Alzheimer’s dis-ease. The distribution of apolipoprotein E poly-morphisms varies among populations. The fre-quency of the e4 polymorphism is about 5% to

7% in Chinese populations, 10% in other Asianand American Indian groups, and 20% to 30%in African Americans and Africans.31 Tacrine,the cholinomimetic drug used to treat Alzhei-mer’s disease, is more effective in individualswho do not carry the e4 polymorphism. Fur-thermore, lorazepam-induced memory impair-ment is greater in elderly individuals carryinge4.31 These polymorphisms also appear to af-fect response to lipid-lowering drugs, includingfibrates and statins, but the data are complexand a clear interpretation has not yet emerged.

RACIAL AND ETHNIC VARIATION INPOLYMORPHISMS IN DRUG METABOLISMHow Genetic Polymorphisms Are Expressed inthe Population

Polymorphisms are alterations in the genesthat potentially alter the activity of the geneproduct—in this instance, an enzyme involvedin drug metabolism. If the gene product re-tains some activity, the genetic polymorphism isreferred to as an active allele (‘allele’ is thegenetic term for a mutant form of a gene; thenative form of a gene is called the wild type).There are also inactive alleles that produce noenzyme at all or a completely inactive enzyme.Less often, multiple copies of the wild typegene or an active allele may occur, which re-sults in greater than normal enzyme activity(referred to as the ultra extensive metabolizerphenotype). Thus, many different polymor-phisms can produce the same few end results:

Table 5. Drugs Metabolized by CYP2C19

Carisoprodol Amitriptyline

Citalopram ClomipramineDiazepam HexobarbitalMephenytoin ImipramineOmeprazole Mephobarbital

Propranolol

Source: Poolsup et al. (2000).16

Table 4. Implications of CYP2D6 Poor Metabolizer Phenotype

Decreased elimination resulting in accumulationof parent compound and toxicity Anti-arrhythmics (sparteine, mexiletine, flecainide)

Beta-blockers (metoprolol, timolol)Neuroleptics (perphenazine)Tricyclic antidepressants (nortriptyline, clomipramine)

Decreased prodrug activation CodeineDecreased elimination of active metabolite ImipramineDecreased elimination of parent compound and

active metaboliteAmitriptyline

Source: Wolf & Smith (1999).30



an enzyme with normal activity, reduced activ-ity, or no activity. Since humans have two cop-ies of every autosomal gene, i.e., one from eachparent, either or both of the copies might be awild type copy or any one of the polymorphicvariants. The resulting phenotype, whether ex-tensive metabolizer or poor metabolizer, de-pends on which combination of two gene cop-ies is present.

This is illustrated in Table 8 for CYP2D6polymorphisms. Combinations of the wild typegene and any of the several common active orinactive alleles still produce the EM phenotypebecause sufficient wild type enzyme is pro-duced from the wild type gene copy. Thus, intotal 81.9% of the White population has theEM phenotype, although this is the result of avariety of genotypes. Combinations of the vari-ous active and inactive alleles produce the poormetabolizer phenotype. The prevalence of thePM phenotype in the White subjects studied inTable 8 is 11.4%, due in most part to combina-

tions of two inactive alleles with each other orwith an active allele.

Racial Variations in CYP2D6 and CYP2D19Polymorphisms

The prevalence of the PM phenotype of boththe CYP2D6 and CYP2C19 drug metabolism sys-tems in different populations is shown in Table9—i.e., Table 9 shows phenotypic frequenciesand not gene frequencies. The prevalence ofthe CYP2D6 poor metabolizer phenotype is inthe range of 0 to 2.1% in Asian populationsand in populations indigenous to the Asiansubcontinent, Egypt, Saudi Arabia, and Pan-ama (Table 9).

The CYP2D6 poor metabolizer phenotype ismore common in White populations (medianprevalence 7.2%). The prevalence in Sub-Saharan Africa is greater than in Asian popula-tions but varies greatly, reaching 18.8% in theSan bushmen. The prevalence in African Amer-icans is 1.9%.

Table 6. Clinically Relevant Polymorphisms of Drug Targets

Mechanism/target Drug Drug effect linked to polymorphism

Receptorsb2 adrenergic receptor Albuterol Response in asthmaticsSerotonin (5-HT2A) receptor Clozapine Altered binding

Enzymes5-Lipoxygenase Zileuton Response in asthmaticsAngiotensin-converting enzyme Enalapril, lisinopril,

captoprilRenoprotective effects, cardiac indices,blood pressure, immunoglobulin Anephropathy

Potassium ChannelsHERG Quinidine Drug-induced long QT syndrome

Source: Evans & Relling (1999).29

Table 7. Polymorphisms of Disease Pathways

Protein (Gene) Drug Pharmacogenetic effect

Apolipoprotein E Tacrine Apo «4 polymorphism is associated with risk of developingAlzheimer’s disease and response to tacrine treatment

Cholesteryl ester transport protein(CETP), lipoprotein lipase (LDL), -fibrinogen

Pravastatin Atherosclerosis progression and response to pravastatin

Source: Kleyn & Vesell (1998),28 Evans & Relling (1999).29



In contrast, the prevalence of the CYP2C19slow metabolizer phenotype is high in Asian pop-ulations (median 15.7%) and in the Asian sub-continent (17.6%) and low in Whites (median2.9%—Table 9). The prevalence in AfricanAmericans (18.5%) is higher than among Tanza-nians (3.6%) and Zimbabweans (4.0%). Theprevalence in Chinese populations refer to themajority ethnic Chinese group (Han). However,China is a multinational country with 55 ethnicminorities in addition to the Han majority. Theprevalence of the CYP2C19 poor metabolizerphenotype is significantly lower in some of thesegroups than in the Han Chinese.33

Racial Variations in AcetylationThe prevalence of the slow acetylator pheno-

type in various populations is shown in Table10. It is roughly 50% in both the African Amer-ican and White populations (median 51% and58%, respectively). The prevalence in Asianpopulations is considerably lower (median22% in Chinese and 10% in Japanese).

CLINICAL RELEVANCE OF GENETICPOLYMORPHISMS

It is important to determine whether a givenpolymorphism has clinical relevance in drugtherapy. Meyer poses four questions to deter-mine the clinical importance of a genetic poly-morphism:17

1) Does the polymorphic pathway of thedrug result in a major difference betweenthe EM and PM phenotypes in the clear-ance or elimination of the drug?

2) Does the drug have a narrow therapeuticindex?

3) Is the dosage of the drug individuallyevaluated on the basis of the therapeuticeffect?

4) Is the drug widely used by many physi-cians or only by a clinical specialist?

First, polymorphisms only have clinical impor-tance when they result in large differences be-

tween the poor metabolizer and extensive me-tabolizer phenotypes—as is the case, forexample, with the psychotropic drugs desipra-mine and perphenazine. Second, pharmacoki-netic differences are relevant chiefly if the drughas a small therapeutic index, e.g., isoprotere-nol, phenytoin, warfarin, clonidine, and quini-dine gluconate. Third, if physicians adjust drugdosage based on the therapeutic effect (as isusual with antihypertensive drugs), then pheno-typic differences are automatically corrected, al-though the physician may not be aware of anypharmacokinetic variation. Fourth, widely pre-scribed drugs such as beta-blockers or tricyclicantidepressants have broader clinical implica-tions because more patients in more populationsubgroups are affected.

Table 8. Many Different Genotypes Produce the SameFew Phenotypes: Prevalence of the Most Common

CYP2D6 Polymorphisms among Unrelated CaucasianSubjects

Genotype* Phenotype% of

Population

wild type / wild type EM 47.6wild type / active allele EM -wild type / inactive allele EM 34.3wild type / amplified allele UEM 6.7active allele / active allele PM -active allele / inactive allele PM 2.9inactive allele / inactive allele PM 8.5

*Each individual has two copies of every gene—one fromeach parent (with the exception of genes on the Y chromo-some). The normal gene is called the wild type, and alteredversions are called alleles. An individual may have anycombination of wild type genes or mutant alleles. Activealleles are altered versions of the wild type gene thatencode mutant CYP2D6 enzymes that retain partial activ-ity. The common active alleles are CYP2D6 A and CYP2D6L. Inactive alleles are versions of the gene that encodeCYP2D6 enzymes with little and sometimes no enzymicactivity. The common inactive alleles are CYP2D6 B andCYP2D6 D (in this allele, the gene is deleted). In the L2polymorphism, an active allele is present in amplified form,i.e., there are multiple copies of the allele; this leads tomore CYP2D6 enzyme being produced and hence theUEM phenotype.EM, extensive metabolism. PM, poor metabolism. UEM,ultra-extensive metabolism.Adapted from Linder et al. (1997).32



DRUGS SHOWING VARYING EFFECTSAMONG RACIAL AND ETHNIC GROUPS

Most pharmacogenetic studies have concen-trated on several groups of drugs and their activ-ity in certain populations. These drug groups in-clude cardiovascular drugs (Table 11) andcentral nervous system (CNS) agents (Table 12).Cross-racial variability in the action of drugs inthese categories is clinically significant, and re-sults from differences in pharmacokinetic orpharmacodynamic factors, or in the pathophysi-ology of disease. The clinical and policy implica-tions of this variability are discussed below.

Cross-Racial Differences in Response toCardiovascular Drugs

Table 11 lists racial and ethnic variation indrug exposure or the clinical response torepresentatives of several classes of cardiovas-cular drugs. The term ‘drug exposure’ refersto the duration and intensity of the body’sexposure to a drug, and is expressed in termsof pharmacokinetic parameters (in Table 11exposure is measured as the area under thetime-blood concentration curve). ACE inhib-itors have greater effects on hypertensionand heart failure in Whites than in African

Table 9. Prevalence of CYP2D6 and CYP2C19 Poor Metabolizer Phenotypes in Various Populations

Population N Populationsa

Poor metabolizer phenotype (%)

Median Range

CYP2D6African (Sub-Saharan)b 6 3.4 1.8-18.8Amerindianc 1 0Asiand 8 0.5 0-2.1Asian Subcontinente 1 0Caucasianf 20 7.2 3.2-10.4Middle East/North Africag 2 1.5 1.4-1.5Polynesian (S. Pacific) 1 0

CYP2C19African (Sub-Saharan)h 3 4.0 3.6-18.5Amerindiani 1 2.0Asianj 6 15.7 5.1-23.6Asian Subcontinentk 2 17.6 14.4-20.8Caucasianl 12 2.9 1.3-6.1Middle East/North Africam 1 2.0Polynesian (S. Pacific) 1 13.6

aNumber of different populations. Where there were two or more studies of the same population (e.g., Chinese), the datawere 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, NewZealand, Polish, Russian (Estonia), Spanish, Swedish, Swiss, Turkish, US.gEgyptian, Saudi Arabian.hAfrican American, Tanzanian, Zimbabwean.iInuit.jChinese (Canada), Chinese (China), Filipino (Saudi Arabia), Indonesian, Japanese, Korean.kIndian, Sinhalese.lCanadian, Danish, Dutch, Estonian, French, Greenlander, Jordanian, Russian (Estonia), Spanish, Swedish, Swiss, US.mSaudi Arabian.Adapted from Poolsup et al. (2000).16



Americans. Similarly, the response to the be-ta-blocker isoproterenol is greater in Whitesthan in African Americans. Conversely, theantihypertensive response to the diuretic hy-drochorothiazide is greater in African Amer-icans, while exposure to the calcium channelblocker nifedipine is lower in Whites than inSouth Asians, Koreans, or Nigerians.

The beta-blocker propranolol is more effectivein reducing blood pressure and heart rate inChinese than in Whites. Patients in China areprescribed much lower doses of propranololthan patients in the United States and Europebecause of a perception that Chinese people re-spond to lower doses. Consistent with this, a studyof the pharmacodynamics of propranolol foundthat, at equivalent blood levels, Chinese men hadgreater sensitivity than White men to proprano-lol’s effects on heart rate and blood pressure.Paradoxically, the Chinese subjects metabolizedpropranolol much more rapidly than the Whitesubjects; the total blood clearance for the Chi-nese was 76% higher, resulting in a substantiallylower area under the time-blood concentrationcurve (AUC). Clearance of propranolol was twotimes greater in Chinese subjects because of theirincreased ability to metabolize the drug, resultingin lower blood concentrations at similar doses.Pharmacokinetic properties, therefore, do notexplain the increased sensitivity of the Chinese.The mechanism for the increased sensitivity isnot clearly determined, but could be because of agreater suppression of renin in the Chinese pop-ulation.34

Antihypertensive Drugs in Black PopulationsHypertension is disproportionately preva-

lent in the Black population and is associatedwith higher incidences of cerebrovascular andrenal complications and left ventricular hyper-trophy. However, the overall risk of coronaryartery disease in the Black male population islower than in White males, particularly in Eu-rope and the Caribbean, and to a lesser extentin the United States.

There are general differences in the patho-physiology of hypertension between the Black

and White populations. Black hypertensives ex-hibit enhanced sodium retention, a higher in-cidence of salt-sensitive hypertension, ex-panded blood volume, more frequentproteinuria, and a higher prevalence of lowblood renin activity40 (although the majority ofrenin may reside in vascular tissue). TheT594M polymorphism in the epithelial sodiumchannel occurs in about 5% of Blacks and ap-pears to contribute to hypertension in theseindividuals.41 These factors may underlie someof the observed differences in the effectivenessof various antihypertensive drugs in Black pop-ulations. Ultimately, the choice of therapy mustbe tailored to the individual patient.

Although there is a long-standing discussionabout the best type of antihypertensive drug touse in Black patients,42 African Americans re-spond to drugs from all classes.15,43 There is nospecific class of antihypertensive drugs that cat-egorically should not be used based on race.Diuretics are frequently used to counteract in-creased salt retention among Blacks, and recentfindings suggest that the potassium-sparing di-uretic amiloride is effective in controllingblood pressure in patients with the T594M

Table 10. Frequency of Poor Acetylator Phenotypes inVarious Populations

Population N Populationsf

Poor metabolizerphenotype (%)

Median Range

Blacka 4 51 42-65Caucasianb 4 58 52-62Chinesec 7 22 13-34Japanesed 2 10 7-12Eskimoe 2 6 5-21

aBlack populations in East Africa, Nigeria, Sudan, and theUnited States.bBritain, Canada, Germany, and United States.cChinese populations in Britain, Canada, Hong Kong,Mainland China, Singapore, Taiwan, and Thailand.dJapan and the United States.eAlaska and Canada.fNumber of different populations. Where there were two ormore studies of the same population, the data were pooledand the median percentage used.Adapted from Wood & Zhou (1991).34



polymorphism.41 Although some studies findthat beta-blockers, ACE inhibitors, and angio-tensin receptor blocking agents do not controlblood pressure in African Americans with thesame degree of effectiveness as in Whites, tar-geted blood pressure levels can usually beachieved by adding a second antihypertensiveagent, such as a low dose diuretic.44,45,46,47,48

The Veterans Administration CooperativeStudies showed that the beta-blocker propra-nolol was less effective among Blacks thanWhites, and that this differential effect waseliminated by addition of a diuretic. Nadolol,atenolol, and penbutolol are also less effectivein Black than in White hypertensives.45 There is

evidence that Blacks may respond differently todifferent beta-blockers. Labetalol (a combinedalpha and beta-blocker) is significantly moreeffective in controlling blood pressure in Blackpatients than propranol or atenolol,49,50 andevidence suggests that bisoprolol may havecomparable effectiveness in Blacks andWhites.45 The Veterans studies also demon-strated that White patients responded better tothe ACE inhibitor captopril than Black pa-tients.39,40 When a diuretic was added, this in-terethnic difference was eliminated.

ACE inhibitors can be as effective in Blacksas calcium channel blockers or diuretics, and insome cases they may be more effective as a first

Table 11. Racial and Ethnic Differences in Response to Cardiovascular Drugs

Drug Comparison groups Drug exposure* Clinical response

ACE inhibitorsEnalapril Blacks vs. Whites N/A Hypertension and

hospitalization for heart failurereduced in Whites but not inBlacks with left ventriculardysfunction

Captopril Blacks vs. Whites N/A Antihypertensive effect greaterin Whites

Beta-blockersIsoproterenol Black vs. White men N/A Vasodilation response to

isoproterenol markedly lower inBlacks

Propranolol Chinese vs. Caucasians Lower in Chinese Chinese twice as sensitive toeffects on blood pressure andheart rate

Blacks vs. Whites N/A Antihypertensive effect greaterin Whites

Calcium channelblockers

Nifedipine South Asians vs.Caucasians

Threefold higher in SouthAsians

N/A

Koreans vs. Caucasians Greater in Koreans N/ANigerians vs.Caucasians

Greater in Nigerians N/A

DiureticsHydrochlorothizide Blacks vs. Whites N/A 71% of Blacks achieved blood

pressure goal vs. 55% ofWhites in VeteransAdministration study

*Statistically significant differences in exposure to drug expressed in terms of a measure of the blood concentration—inthese examples, the area under the blood concentration-time curve (AUC).N/A, not available.Sources: 35,36,37,34,38,39



line treatment. The AASK trial, which studiedthe progression of hypertensive kidney diseaseafter treatment with an ACE inhibitor, a beta-blocker, and a calcium channel blocker, deter-mined that the ACE inhibitor reduced the de-cline in renal function to a greater extent thanthe other drugs or classes.51,52 In hypertensioncomplicated by diabetic nephropathy and inthe presenceof proteinuria, ACE inhibitors arefirst-line agents in Black as well as White pa-tients.40 However, since ACE inhibitors in lowerdoses can be less effective in Black patients,higher doses may be required.53,54,55

ACE inhibitors appear to be less effective inBlack populations in the prevention and treat-ment of heart failure in patients with left ven-tricular dysfunction. In the SOLVD trials, ena-lapril reduced the rate of hospitalization forheart failure in White but not in Black pa-tients.36 (Conversely, the beta-blocker carve-dilol is an equally effective treatment for heartfailure in Black and White patients.56) An-

giodema, a potentially life-threatening side ef-fect of ACE inhibitors, occurs 4.5-fold moreoften in African Americans.

Cross-Racial Differences in Response to CentralNervous System Agents

Tricyclic Antidepressants. Tricyclic antidepres-sants (amitriptyline, clomipramine, desipra-mine, imipramine, and nortriptyline) have anarrow therapeutic index and are metabolizedby CYP2D6. Poor metabolizers and ultra exten-sive metabolizers may have clinical problemswhen these drugs are taken at usually pre-scribed doses. Poor metabolizers often developelevated blood concentrations that may resultin adverse effects. These side effects are rarelylife threatening, but they are sufficiently un-pleasant that problems with patient compli-ance ensue. Ultra-extensive metabolizers, onthe other hand, may not respond to recom-mended doses because drug concentrationsare too low to be efficacious.

Table 12. Racial and Ethnic Differences in Response to Central Nervous System Agents

Drug Comparison groups Exposure* Clinical response

AntidepressantsClomipramine Asians, (Indian, Pakistani) vs.

Whites (English)Greater in Asians (AUC) Higher incidence and severity

of side effects in AsiansNortriptyline Japanese vs. American Greater in Japanese (AUC) N/ABenzodiazepinesAlprazolam Asians vs. Caucasians Lower for Asians (CLs) N/AAntipsychoticsClozapine Korean Americans vs.

CaucasiansN/A Clinically adjusted dose lower

in Koreans, and higher rateof anticholinergic side effects

Haloperidol Orientals (Chinese, Japanese,Filipino, Korean, Vietnamese)vs. Caucasians

No difference Neuroleptic dose and optimalresponse threshold lower forOrientals

Chinese vs. Non-Chinese(Caucasians, Hispanics,Blacks)

Higher mean blood levels inChinese than in Americans(when given same dose)

Clinically adjusted dose lowerfor Chinese than for non-Chinese

Caucasians vs. American-bornAsians vs. foreign-born Asians(Chinese, Filipino, Japanese,Koreans)

Higher for Asians than forCaucasians (Cmax). Similarfor American-born andforeign-born Asians.

No difference in side effects

*Statistically significant differences in exposure, i.e., a measure of the blood concentration: either the area under the bloodconcentration-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



Clinical and pharmacokinetic studies haveevaluated ethnic variations in dose response toclomipramine, desipramine, and nortriptyline.In a study of clomipramine, the blood concen-tration (AUC) was greater in Asians than inWhites after an equivalent dose, and Asians hada higher incidence and severity of drug-relatedside effects (Table 12). Similarly, the bloodconcentration of nortriptyline was found to begreater in Japanese than in American Whites.Pharmacokinetic studies with desipramine inAsians and Whites have not produced consis-tent results. In studies of depressive patients,dosages of tricyclic antidepressants were lowerfor Asians than for White, and Asians re-sponded to lower concentrations of desipra-mine or imipramine.

There are few reliable studies of cross-ethnicdifferences in drug disposition and response totricyclic antidepressants in African and His-panic individuals. Hispanic patients have beenreported to require lower doses of antidepres-sants and to experience more side effects whencompared to Whites. The preponderance ofthe data suggest that, for a given dose of atricyclic antidepressant, African Americansshow higher blood levels and faster therapeuticresponse, but also more toxic side effects com-pared with Whites.57

BenzodiazepinesThe benzodiazepine diazepam is an impor-

tant drug affected by CYP2C19 polymorphisms.However, there have been relatively few studiesof ethnic differences in response to diazepamor other benzodiazepines. Asian psychiatric pa-tients often require lower doses of diazepam,but this may be because of differences in bodyfat rather than to genetic differences in drugmetabolism.16 The clearance of alprazolam,which is metabolized by the CYP3A4 system, issignificantly higher in Whites than in Asians.38

AntipsychoticsCYP2D6 polymorphisms affect the metabo-

lism of antipsychotic drugs such as haloperidoland clozapine. Most studies of ethnicity and

antipsychotic drug response have been con-ducted in Asian and White populations. Thesestudies have in general found that, comparedwith Whites, Asians respond to lower doses ofantipsychotic drugs and develop toxic side ef-fects at lower doses.16,34 Although the data arenot entirely consistent, these results may beattributable to differences in pharmacokinet-ics. Blood levels of haloperidol were higher inChinese or other Asians than in Whites in twostudies (although not in a third). In these stud-ies, the clinically adjusted dose of haloperidolwas lower for Chinese and other Orientals thanfor Whites (Table 12). Similarly, the clinicallyadjusted dose of clozapine was lower in KoreanAmericans than in Whites. There was no differ-ence between American-born and foreign-bornAsians in response to haloperidol (Table 12).

There have been relatively few studies of themechanisms responsible for the differences inclinical response to antipsychotics in AfricanAmerican patients. In a study of trifluoperazineand fluphenzine, the pharmacokinetic param-eters did not differ between African Americansand Whites. However, antipsychotic use (andoften misuse) is more frequent in the AfricanAmerican population. African Americans havealso tended to receive substantially higherdoses of antipsychotics, perhaps because of di-agnoses of more severe illness, but also becauseof the stereotype that African Americans aremore difficult to manage and are less compli-ant.57 Rigorous studies are needed to delineatebiological and cultural mechanisms that mightbe responsible for these clinical practices andto characterize the pharmacokinetics and phar-macodynamics in African American popula-tions of these potent and potentially toxic sub-stances.

Other ethnic groups, such as AshkenaziJews, may also respond differently to antipsy-chotic agents, especially with regard to theside effects profile. Lieberman et al. found thatclozapine, used to treat schizophrenia, was asso-ciated with the development of agranulocytosis in20% of Jewish patients, although this adverse re-action develops in only about 1% of chronic



schizophrenic patients in the general popula-tion.58 Genetic testing revealed that a specifichaplotype (a set of closely linked genes that de-termine different antigens but are inherited as aunit) was found in 83% of patients who devel-oped agranulocytosis. All of the affected Ash-kenazi Jewish patients possessed this haplotype,compared with 8% of these who did not developthe reaction. This haplotype is characteristicallyfound in less than 1% of the White population inthe United States, but occurs in 10% to 12% ofthe Jewish population in Israel and the UnitedStates. The increased susceptibility of AshkenaziJews in this study to the development of clozap-ine-induced agranulocytosis may be a result ofthe high incidence of this haplotype in this eth-nic population.59

AnalgesicsCYP2D6 polymorphisms play a role in the

metabolism of codeine. Approximately 10% ofcodeine is metabolized via the CYP2D6 systemto morphine, from which codeine derives itsanalgesic effect. However, individuals with theCYP2D6 poor metabolizer phenotype cannotmetabolize codeine to morphine and thereforereceive no analgesic or therapeutic effect fromthe drug.60 This may have important clinicalimplications for the 5% to10% of White pa-tients with the CYP2D6 poor metabolizer phe-notype, because codeine is often given as adrug of first choice for treatment of chronicsevere pain. Most East Asians and Whites pos-sess different combinations of CYP2D6 poly-morphisms that confer the extensive metabo-lizer phenotype. The distribution of thesepolymorphisms, however, and the expressionof the phenotype differ among these popula-tions, so that East Asians with the extensivemetabolizer phenotype have lower levels ofCYP2D6 activity than do Whites with this phe-notype. Hence, the production of morphinefrom codeine—and the analgesic effect—islower in Chinese than in Whites with the ex-tensive metabolizer phenotype.38

Finally, in a study of White and Asian (mostlyIndian) immigrants in London, clearance rates

of acetaminophen were significantly higher inWhites. Environmental factors, such as use ofalcohol, tobacco, and oral contraceptives wereassociated with increased clearance rates, butdid not account for all the interethnic differ-ences.61

POLICY IMPLICATIONSPhysicians should be aware of genetic poly-

morphism as an important source of variationin drug response among individuals andshould incorporate genetic factors into dosageconsiderations. Even if the physician is notaware of the underlying pharmacogenetic prin-ciples involved in distinguishing between ge-netic phenotypes, knowledge of the widely vary-ing responses of different ethnic groups tocertain drugs should alert the physician to theneed to individualize therapy and to includeconsideration of the patient’s ethnic or racialorigin.

Cross-racial differences in response to drugsare relevant to the implementation of pharma-ceutical cost control tactics. For example, thedesign of step-care protocols should includedrugs at the first step that enable optimal ther-apy for patients of all races.

Metabolic differences among drugs of thesame class have clear implications for therapeu-tic exchange programs, in which another drugfrom the same therapeutic class is substitutedfor a prescribed drug. Not all individual drugswithin a class are metabolized by pathways sub-ject to functional polymorphism, and somedrugs are not metabolized at all but are ex-creted unchanged. Drugs that are metabolizedchiefly through oxidation or acetylation in theliver are likely to show genetic differences inmetabolism, whereas drugs that are metabo-lized through other pathways, or are not me-tabolized at all, are less likely to show cross-racial variability. As a result, drugs in the sameclass may differ in their susceptibility to racialand ethnic differences in clinical effect. Forexample, the class of benzodiazepines, which isprescribed for anxiety, sleep disorders, andconvulsions, includes drugs that are subject to



differences in metabolism (diazepam, clonaz-epam, nitrazepam) and drugs that are not (tria-zolam, midazolam, lorazepam, temazepam, ox-azepam). Similarly some beta-blockers aresubject to differences in metabolism (metopro-lol, propranolol, timolol, labetalol, pindolol,oxprenolol) and some are not (atenolol, nado-lol). While the cost containment strategy be-hind therapeutic substitution programs seemspractical, this policy may also be shortsighted,counter-effective, or clinically risky for patientsin different racial and ethnic groups. Unfortu-nately, the pharmacokinetics of specific agentsin most drug classes has not yet been studied indifferent racial and ethnic groups. Therefore,it is important that therapeutic substitutionprograms for patients of non-White racial andethnic groups be undertaken with extreme cau-tion.

Substitutions of antihypertensives drugswithin the same class may be particularly prob-lematic for African-American patients. The as-sumption that all beta-blockers are therapeuti-cally equivalent is directly contradicted by thedifferences in clinical efficacy between pro-pranolol and labetalol for African Americanand White hypertensive patients. Hence, thepolicy of substituting within the class of all beta-blockers without consideration for clinical dif-ferences in racial and ethnic response mightplace African-American patients at a higherrisk than Whites for receiving suboptimal ther-apy if propranolol were substituted for labe-talol. Interethnic differences between AfricanAmerican and White patients in response toantihypertensive treatment with beta-blockersalso affect decisions about the cost-effective-ness of such treatment.

Finally, the lack of research on drug re-sponse differences among Hispanics, now thenation’s largest racial or ethnic minority group,is of particular concern for the delivery of qual-ity health care.

The Future of Individualized TherapyTechnological advances in the 1990s have

changed the nature of pharmacogenetic re-

search and its future impact on medicine. Inthe early decades of its existence, pharmacoge-netics focused on the enzymes responsibledrug metabolism. Differences in the genes en-coding these enzymes were inferred from dif-ferences in the structure and activity of theenzymes themselves, i.e., from phenotypic dif-ferences. The frequencies of polymorphisms indrug metabolism enzymes were observed tovary among different populations defined onthe basis of race or ethnicity. Race or ethnicityis, thus, a factor that changes the probabilitythat an individual person will respond to agiven drug. However, “race” is an inaccuratelabel for genetic variations that a given individ-ual might or might not possess.

Two features of the genomics revolution,with the Human Genome Project as its center-piece, have important consequences for therelationship between drug therapy and race orethnicity. First, genetic variations are now de-termined by direct analysis of genes themselvesby determination of their nucleotide se-quences. Gene sequencing is now a rapid andautomated process. Second, the entire spec-trum of genes that determine drug behaviorand sensitivity can now be studied genetically.That is, the effect of the entire genome on drugbehavior can now be determined rather thanthe effect of the individual gene—hence thechange from pharmacogenetics to pharmacog-enomics. It is now possible to take a genetic‘fingerprint’ of an individual and determineprecisely the presence of polymorphisms in thegenes known to be involved in drug interac-tion. Instead of a person’s race being a markerfor the possession of polymorphisms involvedin drug response, a genotypic profile can de-termine with certainty whether or not the indi-vidual possesses these polymorphisms.

In the future, drug treatment will be individ-ually tailored rather than race-based; however,the full impact of these changes will take manyyears to unfold. Genetic fingerprinting usingDNA arrays is already practical, but the knowl-edge base relating genomic variations to drugresponse and disease progression has not been



developed. Observational studies are underway in which DNA fingerprints are being cor-related with data present in medical recordsabout medical history and drug response, andit is expected that the medical records of anentire country (Iceland) will be correlated withgenomic data. These developments will surelyhave a profound impact on the ways in whichnew drugs are developed and used.

Continuing research in pharmacogenomicsis likely to reveal significant and far-ranginginformation regarding interindividual andcross-racial differences in the actions of newand existing drugs. These developments, alongwith the increasing prevalence and influence ofpatients from a variety of races and ethnicitiesand the continued pressure to manage healthcare costs, will require programs having thedual objectives of cost control and individual-ized therapy for a racially and ethnically diversepopulation of Americans. Balancing these two,potentially opposing objectives will challengehealth policy makers in the coming decades.

CONCLUSIONS AND RECOMMENDATIONSAs a result of advances in pharmacogenetics

research, as well as political and social changesaffecting racial and ethnic groups, more con-sideration is being given to the need to individ-ualize drug therapy. Although the precedingreview is not an exhaustive account of clinicaland pharmacological studies involving racialand ethnic variation, it clearly emphasizes therange and scope of the problem. There can beno mistaking the importance of this issue for allhealth care providers. The following recom-mendations offer practical suggestions that canhave positive benefits not only on the quality ofcare provided by health care institutions andphysicians, but also on the control of healthcare costs.

1) Health care institutions should monitor,and restrict if necessary, the practice oftherapeutic substitution of drugs withinthe same drug classes. Patients in partic-ular racial and ethnic groups may be sub-

ject to greater risks than those in othergroups if they are prescribed an “equiva-lent” drug because substantial evidenceindicates that, even within a class, drugeffectiveness and toxicity can vary amongracial and ethnic groups. Institutionaldrug formularies and step-care protocolsshould be broad enough to allow rationalchoices of drugs and dosages for all pa-tients, regardless of race or ethnic origin.

2) Pharmaceutical companies should con-tinue to include significant numbers of pa-tients from varied racial and ethnic back-grounds in drug metabolism and clinicaltrials in instances where genetic polymor-phism for that drug class is relevant. Thevast majority of drug manufacturers testand evaluate new pharmacological com-pounds on population subgroups, includ-ing racial and ethnic subgroups. This islikely to reveal drug actions and side effectsspecific to these groups, and may lead tothe discovery of therapies of specific advan-tage to these populations.

3) Health care providers should give indi-vidualized treatment to each patient andresist the temptation to apply “cookbook”drug therapy that does not take into ac-count racial or ethnic origin. For thepracticing physician, each patient repre-sents a unique and dynamic interactionamong determinants that are both ge-netic and environmental. While it may beimpossible for a physician to anticipatehow a particular patient will respond inevery instance, it is imperative to individ-ualize therapy with respect to the appro-priate choice of both drug and dose.

4) Physicians should be alert to atypicaldrug responses or unexpected side ef-fects when they treat patients from variedracial and ethnic backgrounds. Dosageadjustments should be made for patientsfrom different racial and ethnic groups ifpharmacological evidence supports theadjustment.

5) Finally, and perhaps most important, all



who are involved in patient care shouldbe aware of the growing clinical rele-vance of pharmacogenetics in determin-ing differences in patient responses todrug therapy.

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