Genetic Factors in Drug Metabolism

Recently, the african american Heart Failure Trial (Aa-HeFT)demonstrated that adding isosorbide dinitrate (Isochron) andhydralazine (Aapresoline; brand not available in United States) tostandard therapy for heart failure increases survival in blackpatients with advanced heart failure.37 It has been proposed thatnitric oxide deficiency can result in the progression of heartfailure.38 Patients exhibiting genetic polymorphism may have lessnitric oxide and, thus, may benefit from nitric oxide-enhancingtherapy. Because this study included only black patients, it lackedevidence of differences in response between white and blackamericans. The gene or genes responsible for nitric oxidedeficiency have not been identified in black persons. However,several biologic systems are involved in the pathogenesis of heartfailure, and each is highly polymorphic. Currently, no prospectivestudies are investigating the simultaneous impact of multiplegenetic variants on cardiovascular outcomes. Several genes areassociated with coronary heart disease (CHD). The involvement ofmultiple genes with potential polymorphisms makes predictingpersons at risk of developing CHD highly imprecise. E examples ofgenes affecting CHD include the cholesteryl ester transfer protein,stromelysin-1, beta- fibrinogen, and apolipoprotein e genes.Descriptions of genetic polymorphisms associated with CHD and theirresponse to statin therapy are summarized in Table 4.10,16-25
ASTHMA
Approximately 8 to 10 percent of the U.S. population is affected byasthma. In terms of morbidity and cost, asthma is considered amajor health risk.39 Research has focused on identifying thepotential role of genetics in the pathophysiology and management ofasthma.40-43 Common drugs used to control asthma are beta2 agonists(both short- and long-acting), inhaled corticosteroids, andleukotriene antagonists. Response to asthma medications is highlyvariable, with only 60 to 80 percent of patients derivingtherapeutic benefit.40
Inhaled beta2 agonists, such as albuterol (Proventil), are used tocontrol acute attacks of asthma and are prescribed to be used "asneeded." Several studies have shown that some patients benefit fromuse of short- acting beta2 agonists whereas others do not.22,44This variation in response is partly explained by the alteration inthe amino acid sequence of the protein or altered transcription ofthe beta2 receptors. Patients with the beta2 receptor argininegenotype experience poor asthma control with frequent symptoms anda decrease in scores on forced expiratory volume in one secondcompared with patients who have the glycine genotype.22,45 Studiesshow that 17 percent of whites and 20 percent of blacks carry thearginine genotype.46
Leukotriene (LlT) modifiers (e.g., zileuton [Zyflo], montelukast[Singulair], zafirlukast [Aaccolate]) block the 5-lipoxygenase (5-LOlo) and lTC4 synthase pathways, preventing leukotriene-mediatedbronchoconstriction. 47,48 only a minority of patients benefit fromtreatment with lT receptor agonists. Polymorphism in 5-LO lo andlTC4 synthase pathways has been identified (Table 410,16-25).Aapproximately 5 percent of patients with asthma have the 5-LO lopolymorphism. Patients who had the 5-lo polymorphism showed agreater improvement in their lung function with zafirlukast therapycompared with patients who had the normal 5-lo genotype. Similarly,polymorphisms in the L lTC4 synthase gene may predispose a personto asthma. Patients with the variant lTC4 synthase genotype havehigher levels of cysteinyl leukotrienes, which have been linkedwith severe asthma. The use of lT modifiers in this population maybe beneficial.24,49
Variation in the genes involved in the biologic action of inhaledcorticosteroids may explain the variability to response and adverseeffects to inhaled corticosteroids. Polymorphisms in corticotropin-releasing hormone receptor-1 and T-box expressed in T cells havebeen associated with improved response in patients withasthma.50,51 Aalthough these findings are promising in predictingtherapeutic response to asthma medication, their usefulness inclinical practice is still under investigation.
Warfarin
Warfarin dosing can be challenging because of its narrowtherapeutic index and the serious risk of bleeding with overdosage.Typically, warfarin dosing is individualized based on sex, age,vitamin K intake, drug interactions, and disease states. Dosingadjustments are made according to the desired International Nnormalized Ratio. Eenvironmental and genetic factors can influencewarfarin response. Several studies have focused on CYP2C9polymorphisms to explain patient variability with warfarin therapy.O only about 10 percent of dosage variation in warfarin can beexplained by CYP2C9 polymorphisms.
Warfarin exerts its anticoagulant effects by inhibiting hepaticvitamin K epoxide reductase, an enzyme involved in the synthesis ofvarious clotting factors. Polymorphisms in the vitamin K epoxidereductase complex subunit 1 (VKORC1) gene have been identified andare believed to contribute to the variability in warfarinresponsiveness. 10 Understanding environmental and genetic factorswill allow the physician to more accurately dose warfarin andimprove anticoagulation control.
Limitations of the Current Literature on Pharmacogenomics
Most pharmacodynamic studies have been relatively small and thepopulations studied are not always well characterized. E ethniccategories (e.g., A asians, blacks, whites) include persons fromwidely diverse geographic and sociocultural backgrounds withvarying genetic composition, and the results might not apply to allmembers of each ethnic population. Typically, pharmacokineticvariability is no greater than pharmacodynamic variability;however, in most studies, only selected pharmacokinetic parameterswere examined.
Use of genotyping is more accurate than race or ethnic categoriesto identify variations in drug response.52 Unlike other influenceson drug response, genetic factors remain constant throughout life.The use of pharmacogenetic information to support drug selectionand dosing is emerging. Commercial testing is available for drug-metabolizing enzymes and some pharmacodynamic targets such asVKORC1, stromelysin- 1, and apolipoprotein e.53,54 Prospectivegenetic testing would be beneficial for drugs for which a cleargenotype-response relationship has been demonstrated, such aswarfarin (CYP2C9, VKORC1) and proton pump inhibitors (CYP2C19). TheU.S. Food and Drug administration has suggested relabeling warfarinto include genetic information to guide initial dosing.55
The authors thank Ganesh Cherala, PhD, for reviewing themanuscript, and Nathan Thomas for his technical expertise in thepreparation of the manuscript.
This is one in a series of "Clinical Pharmacology" articlescoordinated by Allen F. Shaughnessy, PharmD, Tufts UniversityFamily Medicine Residency at Cambridge Health Alliance, Malden,Mass.
Table 1. Factors Influencing Drug Response
Intrinsic
Genetic
Absorption, distribution, metabolism, excretion
Body weight
Genetic conditions
Genetic polymorphism of drug-metabolizing enzymes
Height
Race
Receptor sensitivity
Sex
Physiologic
Absorption, distribution, metabolism, excretion
Age
Alcohol
Body weight
Cardiovascular function
Diet
Diseases/conditions
Height
Kidney function
Liver function
Receptor sensitivity
Smoking
Stress
Extrinsic
Alcohol
Climate
Culture
Educational status
Language
Socioeconomic factors
Definition/diagnostics
Diet
Diseases/conditions
Drug adherence
Medical practices
Pollution
Smoking
Stress
Sunlight
Therapeutic approach
Adapted from the U.S. Food and Drug Administration, U.S. Dept. ofHealth and Human Services. International Conference onHarmonisation: guidance on ethnic factors in the acceptability offoreign clinical data; availability. Federal Register1998;63(111):31790-31796. http://www.fda.gov/cder/guidance/2293fnl.pdf. Accessed October 17, 2007.
Prospective genetic testing could be beneficial for drugs for whicha clear genotype-response relationship has been demonstrated.
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DONNA J. BELLE, PhD, RPh, and HARLEEN SINGH, PharmD, Oregon StateUniversity College of Pharmacy, Portland Campus at Oregon Health &Science University, Portland, Oregon
The Authors
DONNA J. BELLE, PhD, RPh, was an assistant research professor ofpharmacokinetics in the College of Pharmacy, Oregon StateUniversity, Portland, at the time she coauthored this article. Dr.Belle received her doctorate degree from the School of Pharmacy atWest Virginia University, Morgantown, and completed a postdoctoralresearch fellowship in the Department of Drug Disposition at EliLilly and Company, Indianapolis, Ind.
HARLEEN SINGH, PharmD, is an assistant professor of pharmacy in theDepartment of Pharmacy Practice, College of Pharmacy, Oregon StateUniversity. Dr. Singh received her doctor of pharmacy degree fromOhio State University College of Pharmacy, Columbus, where she alsocompleted a residency in adult medicine. Address correspondence toHarleen Singh, PharmD, Oregon State University College of Pharmacy,3303 SW Bond Ave., CH12C, Portland, OR 97239 (e-mail:singhh@ohsu.edu). Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
Copyright American Academy of Family Physicians Jun 1, 2008
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