Genetic Factors in Drug Metabolism



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Patients vary widely in their response to drugs. Having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is important when assessing ethnic differences in drug response. Genetic factors can account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors) have been identified. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react differently to various drugs and to make better decisions about therapy. Ultimately, this understanding may shift the medical paradigm to highly individualized therapeutic regimens.

Although patient response to drugs varies widely and the reasons for this are diverse and complex, experts estimate that genetic factors account for 20 to 95 percent of patient variability in response to individual drugs.1  Genetic influences on drug metabolism interact with other intrinsic (i.e., physiologic) and extrinsic (i.e., cultural, behavioral, and environmental) characteristics of a person to determine the outcome from treatment with any pharmacologic agent (Table 1).2

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidencerating References

Physicians should consider the potential for genetic factors (intrinsic and extrinsic) to influence drug response.

C

2

When a clear genotype-response relationship has been identified and commercial testing is available, pharmacogenetic testing is preferable to the use of ethnic or race categories to individualize therapy.

C

1012, 54, 55


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp.orp/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidencerating References

Physicians should consider the potential for genetic factors (intrinsic and extrinsic) to influence drug response.

C

2

When a clear genotype-response relationship has been identified and commercial testing is available, pharmacogenetic testing is preferable to the use of ethnic or race categories to individualize therapy.

C

1012, 54, 55


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp.orp/afpsort.xml.

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. of Health and Human Services. International Conference on Harmonisation: guidance on ethnic factors in the acceptability of foreign clinical data; availability. Federal Register 1998;63(111):31790–31796. http://www.fda.gov/cder/guidance/2293fnl.pdf. Accessed October 17, 2007.

Table 1   Factors Influencing Drug Response

View Table

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. of Health and Human Services. International Conference on Harmonisation: guidance on ethnic factors in the acceptability of foreign clinical data; availability. Federal Register 1998;63(111):31790–31796. http://www.fda.gov/cder/guidance/2293fnl.pdf. Accessed October 17, 2007.

Although still in its infancy, the field of pharmacogenetics and pharmacogenomics already provides useful clinical information to enhance patient care and offers a growing potential to individualize drug therapy and improve clinical outcomes. This article reviews the leading areas in which genetic variations currently affect treatment and indicates a need for physicians to monitor this topic as genomic-based treatment guidelines become available.

Definitions

The study of genetic variations in drug response is called pharmacogenetics when studying an individual gene, or pharmacogenomics when studying all genes. A person's genotype is his or her genetic makeup. The term can pertain to all genes or to a specific gene. The phenotype is a person's outward physical appearance or function resulting from the interaction between the genotype and the environment. Genetic polymorphisms are naturally occurring variants in gene structure that occur in more than 1 percent of the population. Polymorphisms may influence a drug's action by changing its pharmacokinetics or its pharmacodynamics.

Pharmacokinetics

Pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion. These processes determine the fate of a drug in the body. A combination of metabolism and excretion constitutes drug elimination from the body.

The main routes of drug elimination are metabolism (often in the liver) and renal excretion. Genetic polymorphisms have been identified for many drug-metabolizing enzymes, including the cytochrome P450 (CYP450) enzymes. This gives rise to distinct population phenotypes of persons who have metabolism capabilities ranging from extremely poor to extremely fast. The large range of incidence of common CYP polymorphisms in selected population groups is illustrated in Table 2.39  Some potential clinical consequences of these polymorphisms are listed in Table 3.

Table 2

Incidence of Cytochrome P450 Metabolizer Phenotypes Among Ethnic Groups

Enzyme Metabolizer phenotype Population frequency (%)
Asians Blacks Whites

CYP2C9

Poor

0.43

0.04

1.04

Intermediate

3.54

134

334

Ultrarapid

CYP2C19

Poor

18 to 233,5

1.2 to 5.35,6

2.0 to 5.03,5

Intermediate

307

297,8

187

Ultrarapid

CYP2D6

Poor

1.0 to 4.83,5,8

1.9 to 7.35,6,8

7.0 to 103,8

Intermediate

518

309

1.0 to 2.08

Ultrarapid

0.9 to 218

4.98

1.0 to 5.08


note: Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.

CYP = cytochrome P450.

Information from references 3 through 9.

Table 2   Incidence of Cytochrome P450 Metabolizer Phenotypes Among Ethnic Groups

View Table

Table 2

Incidence of Cytochrome P450 Metabolizer Phenotypes Among Ethnic Groups

Enzyme Metabolizer phenotype Population frequency (%)
Asians Blacks Whites

CYP2C9

Poor

0.43

0.04

1.04

Intermediate

3.54

134

334

Ultrarapid

CYP2C19

Poor

18 to 233,5

1.2 to 5.35,6

2.0 to 5.03,5

Intermediate

307

297,8

187

Ultrarapid

CYP2D6

Poor

1.0 to 4.83,5,8

1.9 to 7.35,6,8

7.0 to 103,8

Intermediate

518

309

1.0 to 2.08

Ultrarapid

0.9 to 218

4.98

1.0 to 5.08


note: Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.

CYP = cytochrome P450.

Information from references 3 through 9.

Table 3

Clinical Consequence of Metabolizer Phenotypes on Drug Response

Drug type Metabolizer phenotype Effect on drug metabolism Potential consequence

Prodrug, needs metabolism to work (e.g., codeine metabolized to morphine)

Poor to intermediate

Slow

Poor drug efficacy, patient at risk of therapeutic failure Accumulation of prodrug, patient at increased risk of drug-induced side effects

Ultrarapid

Fast

Good drug efficacy, rapid effect

Active drug metabolized to inactive drug (e.g., omeprazole [Prilosec] metabolized to 5-hydroxyomeprazole)

Poor to intermediate

Slow

Good drug efficacy Accumulation of active drug, patient at increased risk of drug-induced side effects Patient requires lower dosage

Ultrarapid

Fast

Poor drug efficacy, patient at risk of therapeutic failure Patient requires higher dosage


note: Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.

Table 3   Clinical Consequence of Metabolizer Phenotypes on Drug Response

View Table

Table 3

Clinical Consequence of Metabolizer Phenotypes on Drug Response

Drug type Metabolizer phenotype Effect on drug metabolism Potential consequence

Prodrug, needs metabolism to work (e.g., codeine metabolized to morphine)

Poor to intermediate

Slow

Poor drug efficacy, patient at risk of therapeutic failure Accumulation of prodrug, patient at increased risk of drug-induced side effects

Ultrarapid

Fast

Good drug efficacy, rapid effect

Active drug metabolized to inactive drug (e.g., omeprazole [Prilosec] metabolized to 5-hydroxyomeprazole)

Poor to intermediate

Slow

Good drug efficacy Accumulation of active drug, patient at increased risk of drug-induced side effects Patient requires lower dosage

Ultrarapid

Fast

Poor drug efficacy, patient at risk of therapeutic failure Patient requires higher dosage


note: Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.

Cytochrome P450 2C9 (CYP2C9)

The CYP2C9 enzyme is involved in the metabolism of many common drugs such as glipizide (Glucotrol), tolbutamide (Orinase; brand not available in United States), losartan (Cozaar), phenytoin (Dilantin), and warfarin (Coumadin). The phenotypes CYP2C9*2 and CYP2C9*3 are the two most common variations and are associated with reduced enzymatic activity. CYP2C9 is the principal enzyme responsible for the metabolism of S-warfarin. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearance. Clinical studies have shown that these persons require lower dosages of warfarin and are at an increased risk of excessive anticoagulation.10,11

Cytochrome P450 2C19 (CYP2C19)

The CYP2C19 enzyme metabolizes many drugs, including proton pump inhibitors, citalopram (Celexa), diazepam (Valium), and imipramine (Tofranil). More than 16 variations of CYP2C19, associated with deficient, reduced, normal, or increased activity, have been identified. Genotyping for CYP2C19*2 and CYP2C19*3 identifies most CYP2C19 poor metabolizers. The CYP2C19*17 variant is associated with ultrarapid metabolizers and seems relatively common in Swedes (18 percent), Ethiopians (18 percent), and Chinese (4 percent).12 The proton pump inhibitor omeprazole (Prilosec) is primarily metabolized by CYP2C19 to its inactive metabolite, 5-hydroxyome-prazole. Persons who are CYP2C19 poor metabolizers can have fivefold higher blood concentrations of omeprazole and experience superior acid suppression and higher cure rates than the rest of the population. Conversely, blood concentrations of omeprazole are predicted to be 40 percent lower in ultrarapid metabolizers than in the rest of the population, thus putting persons with the CYP2C19 ultrarapid metabolizers phenotype at risk of therapeutic failure.12

Cytochrome P450 2D6 (CYP2D6)

The enzyme CYP2D6 is involved in the metabolism of an estimated 25 percent of all drugs. More than 75 allelic variants have been identified, with enzyme activities ranging from deficient to ultrarapid. The most common variants associated with poor metabolizer phenotype are CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 in whites and CYP2D6*17 in blacks. Codeine is metabolized by CYP2D6 to its active metabolite, morphine. Clinical studies have shown that CYP2D6 poor metabolizers have poor analgesic response as a result of the reduced conversion of codeine to morphine. Conversely, CYP2D6 ultrarapid metabolizers quickly convert codeine to morphine and have enhanced analgesic response.13

The activity of drug-metabolizing enzymes may be induced or inhibited by many other intrinsic and extrinsic factors, including comorbid conditions, use of other medications, smoking, alcohol intake, and dietary factors.

Pharmacodynamics

Pharmacodynamics is the study of the pharmacologic effect resulting from the interaction between the drug and the biologic system. The relationship between drug concentration and the observed pharmacologic response depends on the drug's mechanism of action. The pharmacologic response to a drug may be mediated through a direct effect, such as binding with a specific receptor, or an indirect effect, such as inhibiting an enzyme in a protein synthesis pathway.

Pharmacogenomics in Common Conditions

CARDIOVASCULAR CONDITIONS

Hypertension is a major risk factor for cardiovascular morbidity and mortality.14 Despite the availability of several pharmacologic treatment options for hypertension, only 34 percent of North Americans are achieving target blood pressure goals, and preventing cardiovascular complications is still a notable challenge.15 Extrinsic (e.g., increased sodium intake, decreased calcium and potassium intake, psychosocial stressors) and intrinsic factors (e.g., low plasma renin activity, higher prevalence of expanded plasma volume, reduced sodium-potassium adenosinetri-phosphatase activity, increased intracellular sodium concentrations, elevated fasting insulin levels) may explain the potentially different pathophysiology of hypertension in blacks and whites.16 This has led to the discovery of candidate genes for hypertension (Table 410,1625). Polymorphism in these genes may be responsible for the high prevalence and increased severity of hypertension in black persons.16,2628 The enhanced effects of diuretics in blacks are likely related to many of the extrinsic and intrinsic factors listed above.16,26

Table 4

Genetic Polymorphisms in Drug Receptor Genes Associated with Drug Response

Gene Drug class (drug) Response

ACE

ACE inhibitors, ARBs, statins (fluvastatin [Lescol]), and fibrates (gemfibrozil [Lopid])

Greater blood pressure reduction 17 Greater LDL cholesterol reduction, increase in HDL cholesterol with statins and fibrates

Alpha-adducin

Diuretics (hydrochlorothiazide)

Better blood pressure control with diuretics and fewer cardiovascular events16,18

Angiotensinogen

ACE inhibitors and ARBs (irbesartan [Avapro])

Greater reduction in blood pressure and left ventricle mass with ACE inhibitors and ARBs19

Apolipoprotein E

Statins (simvastatin [Zocor])

Greater mortality reduction with simvastatin20

Beta-fibrinogen

Statins (pravastatin [Pravachol])

Reduction in coronary atherosclerosis21

β1-adrenergic receptors

Beta blockers (metoprolol [Lopressor])

Greater reduction in blood pressure

β2-adrenergic receptors

Beta2-adrenergic agonists (albuterol [Proventil])

May affect survival in heart failure Positive response to bronchodilator therapy22

Cholesteryl ester transfer protein

Statins (pravastatin) Fibrates (gemfibrozil)

Greater effects of pravastatin on slowing coronary atherosclerosis23 Greater reductions in triglycerides

Leukotriene C4 synthase

Leukotriene receptor antagonists (zafirlukast [Accolate])

Improvement in FEV124

5-lipoxygenase

Leukotriene receptor antagonists

May affect disease predisposition of asthma

Stromelysin-1

Statins (i.e., pravastatin)

Pravastatin reduced the incidence of coronary artery restenosis and repeat angioplasty25

Vitamin K epoxide reductase complex subunit 1

Warfarin (Coumadin)

Less variability in dose response10


ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FEV1 = forced expiratory volume in one second; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Information from references 10, and 16 through 25.

Table 4   Genetic Polymorphisms in Drug Receptor Genes Associated with Drug Response

View Table

Table 4

Genetic Polymorphisms in Drug Receptor Genes Associated with Drug Response

Gene Drug class (drug) Response

ACE

ACE inhibitors, ARBs, statins (fluvastatin [Lescol]), and fibrates (gemfibrozil [Lopid])

Greater blood pressure reduction 17 Greater LDL cholesterol reduction, increase in HDL cholesterol with statins and fibrates

Alpha-adducin

Diuretics (hydrochlorothiazide)

Better blood pressure control with diuretics and fewer cardiovascular events16,18

Angiotensinogen

ACE inhibitors and ARBs (irbesartan [Avapro])

Greater reduction in blood pressure and left ventricle mass with ACE inhibitors and ARBs19

Apolipoprotein E

Statins (simvastatin [Zocor])

Greater mortality reduction with simvastatin20

Beta-fibrinogen

Statins (pravastatin [Pravachol])

Reduction in coronary atherosclerosis21

β1-adrenergic receptors

Beta blockers (metoprolol [Lopressor])

Greater reduction in blood pressure

β2-adrenergic receptors

Beta2-adrenergic agonists (albuterol [Proventil])

May affect survival in heart failure Positive response to bronchodilator therapy22

Cholesteryl ester transfer protein

Statins (pravastatin) Fibrates (gemfibrozil)

Greater effects of pravastatin on slowing coronary atherosclerosis23 Greater reductions in triglycerides

Leukotriene C4 synthase

Leukotriene receptor antagonists (zafirlukast [Accolate])

Improvement in FEV124

5-lipoxygenase

Leukotriene receptor antagonists

May affect disease predisposition of asthma

Stromelysin-1

Statins (i.e., pravastatin)

Pravastatin reduced the incidence of coronary artery restenosis and repeat angioplasty25

Vitamin K epoxide reductase complex subunit 1

Warfarin (Coumadin)

Less variability in dose response10


ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FEV1 = forced expiratory volume in one second; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Information from references 10, and 16 through 25.

Typically, black patients require a high dosage of angiotensin-converting enzyme (ACE) inhibitors or combined therapy with low-dose diuretics to reduce blood pressure effectively.29 Although the risk of ACE-related angioedema is generally low, there is some evidence that it is more common in blacks.30 Despite the differences between black persons and other ethnic groups, ACE inhibitors have proven highly effective in reducing morbidity and mortality in patients with hypertension who present with other comorbidities such as heart failure, diabetic nephropathy, and myocardial infarction.14

Advances in drug therapy have helped reduce mortality in many patients with heart failure, but it is unclear whether all population groups have benefited. Beta blockers and ACE inhibitors are the standard of care in patients with heart failure.31 Therapeutic outcomes have been highly variable, possibly secondary to genetic variability in β-adrenergic receptors, the renin-angiotensin-aldosterone system, the endothelin system, and endothelial nitrogen monoxide synthase.32 One of the most important genetic polymorphisms studied in heart failure is an insertion/deletion (I/D) polymorphism of the ACE gene. Persons who are D carriers have higher ACE activity and are at increased risk of developing cardiovascular disease.33,34 Similarly, the response to beta blockers is highly variable in patients with heart failure.35,36

Recently, the African American Heart Failure Trial (A-HeFT) demonstrated that adding isosorbide dinitrate (Isochron) and hydralazine (Apresoline; brand not available in United States) to standard therapy for heart failure increases survival in black patients with advanced heart failure.37 It has been proposed that nitric oxide deficiency can result in the progression of heart failure.38 Patients exhibiting genetic polymorphism may have less nitric oxide and, thus, may benefit from nitric oxide–enhancing therapy. Because this study included only black patients, it lacked evidence of differences in response between white and black Americans. The gene or genes responsible for nitric oxide deficiency have not been identified in black persons. However, several biologic systems are involved in the pathogenesis of heart failure, and each is highly polymorphic. Currently, no prospective studies are investigating the simultaneous impact of multiple genetic variants on cardiovascular outcomes.

Several genes are associated with coronary heart disease (CHD). The involvement of multiple genes with potential polymorphisms makes predicting persons at risk of developing CHD highly imprecise. Examples of genes affecting CHD include the cholesteryl ester transfer protein, stromelysin-1, beta-fibrinogen, and apolipoprotein E genes. Descriptions of genetic polymorphisms associated with CHD and their response to statin therapy are summarized in Table 4.10,1625

ASTHMA

Approximately 8 to 10 percent of the U.S. population is affected by asthma. In terms of morbidity and cost, asthma is considered a major health risk.39 Research has focused on identifying the potential role of genetics in the pathophysiology and management of asthma.4043 Common drugs used to control asthma are beta2 agonists (both short- and long-acting), inhaled corticosteroids, and leukotriene antagonists. Response to asthma medications is highly variable, with only 60 to 80 percent of patients deriving therapeutic benefit.40

Inhaled beta2 agonists, such as albuterol (Proventil), are used to control acute attacks of asthma and are prescribed to be used “as needed.” Several studies have shown that some patients benefit from use of short-acting agonists whereas others do beta2 not.22,44 This variation in response is partly explained by the alteration in the amino acid sequence of the protein or altered transcription of the beta2 receptors. Patients with the beta2 receptor arginine genotype experience poor asthma control with frequent symptoms and a decrease in scores on forced expiratory volume in one second compared with patients who have the glycine genotype.22,45 Studies show that 17 percent of whites and 20 percent of blacks carry the arginine genotype.46

Leukotriene (LT) modifiers (e.g., zileuton [Zyflo], montelukast [Singulair], zafirlukast [Accolate]) block the 5-lipoxygenase (5-LO) and LTC4 synthase pathways, preventing leukotriene-mediated bronchoconstriction.47,48 Only a minority of patients benefit from treatment with LT receptor agonists. Polymorphism in 5-LO and LTC4 synthase pathways has been identified (Table 410,1625). Approximately 5 percent of patients with asthma have the 5-LO polymorphism. Patients who had the 5-LO polymorphism showed a greater improvement in their lung function with zafirlukast therapy compared with patients who had the normal 5-LO genotype. Similarly, polymorphisms in the LTC4 synthase gene may predispose a person to asthma. Patients with the variant LTC4 synthase genotype have higher levels of cysteinyl leukotrienes, which have been linked with severe asthma. The use of LT modifiers in this population may be beneficial.24,49

Variation in the genes involved in the biologic action of inhaled corticosteroids may explain the variability to response and adverse effects to inhaled corticosteroids. Polymorphisms in corticotropin-releasing hormone receptor-1 and T-box expressed in T cells have been associated with improved response in patients with asthma.50,51 Although these findings are promising in predicting therapeutic response to asthma medication, their usefulness in clinical practice is still under investigation.

Warfarin

Warfarin dosing can be challenging because of its narrow therapeutic 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. Dosing adjustments are made according to the desired International Normalized Ratio. Environmental and genetic factors can influence warfarin response. Several studies have focused on CYP2C9 polymorphisms to explain patient variability with warfarin therapy. Only about 10 percent of dosage variation in warfarin can be explained by CYP2C9 polymorphisms.

Warfarin exerts its anticoagulant effectsby inhibiting hepatic vitamin K epoxide reductase, an enzyme involved in the synthesis of various clotting factors. Polymorphisms in the vitamin K epoxide reductasecomplex subunit 1 (VKORC1) gene havebeen identified and are believed to contribute to the variability in warfarin responsiveness.10 Understanding environmental and genetic factors will allow the physician to more accurately dose warfarin and improve anticoagulation control.

Limitations of the Current Literature on Pharmacogenomics

Most pharmacodynamic studies have been relatively small and the populations studied are not always well characterized. Ethnic categories (e.g., Asians, blacks, whites) include persons from widely diverse geographic and sociocultural backgrounds with varying genetic composition, and the results might not apply to all members of each ethnic population. Typically, pharmacokinetic variability is no greater than pharmacodynamic variability; however, in most studies, only selected pharmacokinetic parameters were examined.

Use of genotyping is more accurate than race or ethnic categories to identify variations in drug response.52 Unlike other influences on drug response, genetic factors remain constant throughout life. The use of pharmacogenetic information to support drug selection and dosing is emerging. Commercial testing is available for drug-metabolizing enzymes and some pharmacodynamic targets such as VKORC1, stromelysin-1, and apolipoprotein E.53,54 Prospective genetic testing would be beneficial for drugs for which a clear genotype-response relationship has been demonstrated, such as warfarin (CYP2C9, VKORC1) and proton pump inhibitors (CYP2C19). The U.S. Food and Drug Administration has suggested relabeling warfarin to include genetic information to guide initial dosing.55

The Authors

DONNA J. BELLE, PhD, RPh, was an assistant research professor of pharmacokinetics in the College of Pharmacy, Oregon State University, Portland, at the time she coauthored this article. Dr. Belle received her doctorate degree from the School of Pharmacy at West Virginia University, Morgantown, and completed a postdoctoral research fellowship in the Department of Drug Disposition at Eli Lilly and Company, Indianapolis, Ind.

HARLEEN SINGH, PharmD, is an assistant professor of pharmacy in the Department of Pharmacy Practice, College of Pharmacy, Oregon State University. Dr. Singh received her doctor of pharmacy degree from Ohio State University College of Pharmacy, Columbus, where she also completed a residency in adult medicine.

Address correspondence to Harleen 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.

The authors thank Ganesh Cherala, PhD, for reviewing the manuscript, and Nathan Thomas for his technical expertise in the preparation of the manuscript.

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This is one in a series of “Clinical Pharmacology” articles coordinated by Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Mass.



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