Key Points
-
Variability in response to therapy is an expected feature of most drug treatments.
-
Pharmacokinetic variability arises because of variable delivery of a dose of a drug to target sites; that is, variability in the relationship between drug dose and plasma and tissue drug concentrations.
-
Pharmacodynamic variability arises because of variability in the relationship between drug concentration and effect.
-
In either case, variants in individual genes that mediate drug concentrations or their effects are increasingly being recognized as sources of variable drug action — 'pharmacogenetics'.
-
The sequencing of the human genome now raises the possibility of identifying many genetic variants, each contributing to overall variability in drug action: this is one definition of 'pharmacogenomics.'
-
We propose an algorithm for use in the pharmacogenomic profiling of adverse responses to drug action.
-
Although the vision of choosing 'personalized medicines' based on individual genetic profiles is an appealing one, substantial obstacles will need to be overcome if this is to become practical: these include logistic, analytical, biostatistical and ethical issues.
Abstract
It is almost axiomatic that patients vary widely in their beneficial responses to drug therapy, and serious and apparently unpredictable adverse drug reactions continue to be a major public health problem. Here, we discuss the concept that genetic variants might determine much of this variability in drug response, and propose an algorithm to enable further evaluation of the benefits and pitfalls of this enticing possibility.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kennedy, D. L., Johnson, J. M. & Nightingale, S. L. Monitoring of adverse drug events in hospitals. JAMA 266, 2878 (1991).
Classen, D. C., Pestotnik, S. L., Evans, R. S., Lloyd, J. F. & Burke, J. P. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 277, 301–306 (1997).
Dormann, H. et al. Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting. Drug Saf. 22, 161–168 (2000).
Brewer, T. & Colditz, G. A. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 281, 824–829 (1999).
Phillips, K. A., Veenstra, D. L., Oren, E., Lee, J. K. & Sadee, W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286, 2270–2279 (2001).
Motulsky, A. G., Harper, P. S., Bobrow, M. & Scriver, C. in Pharmacogenetics 1st edn (ed. Weber, W. W.) 1–20 (Oxford Univ. Press, New York, 1997).
Beutler, E., Dern, R. J. & Alving, A. S. The hemolytic effect of primaquine. VI. An in vitro test for sensitivity of erythrocytes to primaquine. J. Lab. Clin. Med. 45, 40–50 (1955).
Price-Evans, D. A., Manley, F. A. & McKusick, V. A. Genetic control of isoniazid metabolism in man. Br. Med. J. 2, 485–491 (1960).
Bönicke, R. & Lisboa, B. P. Uber die Erbbedingtheit der intraindividuellen Konstantz der Isoniazidausscheidung beim Menshen (Untersuchen an eineiggen und zweieiggen Zwilligen). Naturwissenschafften 44, 314 (1957).
Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).
Roses, A. D. Pharmacogenetics and the practice of medicine. Nature 405, 857–865 (2000).
Meyer, U. A. Pharmacogenetics and adverse drug reactions. Lancet 356, 1667–1671 (2000).
Woosley, R. L. et al. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N. Engl. J. Med. 298, 1157–1159 (1978).
Grant, D. M., Blum, M. & Meyer, U. A. Polymorphisms of N-acetyltransferase genes. Xenobiotica 22, 1073–1081 (1992).
Mahgoub, A., Idle, R. J., Dring, L. G., Lancaster, R. & Smith, R. L. Polymorphic hydroxylation of debrisoquine in man. Lancet 2, 584–586 (1977).Initial description of the clinical importance of the CYP2D6 polymorphism in drug disposition and drug action.
Eichelbaum, M., Spannbrucker, N., Steincke, B. & Dengler, H. J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 16, 183–187 (1979).
Caraco, Y., Sheller, J. & Wood, A. J. Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects. J. Pharmacol. Exp. Ther. 290, 413–422 (1999).
Brosen, K., Zeugin, T. & Meyer, U. A. Role of P450IID6, the target of the sparteine–debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin. Pharmacol. Ther. 49, 609–617 (1991).
Lee, J. T. et al. The role of genetically determined polymorphic drug metabolism in the β-blockade produced by propafenone. N. Engl. J. Med. 322, 1764–1768 (1990).
Lennard, M. S. et al. Oxidation phenotype — a major determinant of metoprolol metabolism and response. N. Engl. J. Med. 307, 1558–1560 (1982).
Meyer, U. A. & Zanger, U. M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu. Rev. Pharmacol. Toxicol. 37, 269–296 (1997).
Aithal, G. P., Day, C. P., Kesteven, P. J. & Daly, A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).
Furuta, T. et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann. Intern. Med. 129, 1027–1030 (1998).
Weinshilboum, R. Methyltransferase pharmacogenetics. Pharmacol. Ther. 43, 77–90 (1989).
Ando, Y. et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 60, 6921–6926 (2000).
Glatt, H. et al. Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat. Res. 482, 27–40 (2001).
Forbat, A., Lond, M. B., Lehmann, H. & Silk, E. Prolonged apnea following injection of succinylcholine. Lancet 2, 1067–1068 (1953).
Whittaker, M. Genetic aspects of succinylcholine sensitivity. Anesthesiology 32, 143–150 (1970).
Vandel, S. et al. Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsychobiology 25, 202–207 (1992).
Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. J. Am. Med. Assoc. 269, 1532–1536 (1993).Identification of the pharmacokinetic and ion-channel blocking mechanisms that underlie the potentially fatal cardiotoxicity that is associated with the widely used antihistamine terfenadine.
Fromm, M. F., Kim, R. B., Stein, C. M., Wilkinson, G. R. & Roden, D. M. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99, 552–557 (1999).
Kim, R. B. et al. P-glycoprotein transporter limits oral absorption and brain entry of HIV protease inhibitors. J. Clin. Invest. 101, 289–294 (1998).HIV-protease inhibitors access the CNS in mice with disrupted P-glycoprotein, a potential explanation for the CNS as a viral 'sanctuary site' in protease-inhibitor therapy.
Hoffmeyer, S. et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA 97, 3473–3478 (2000).
Kim, R. B. et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70, 189–199 (2001).
Schinkel, A. H. et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77, 491–502 (1994).
Kuehl, P. et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet. 27, 383–391 (2001).
Lehmann, J. M. et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016–1023 (1998).Regulation of expression of functionally normal genes as a mechanism that underlies drug action.
Smirlis, D., Muangmoonchai, R., Edwards, M., Phillips, I. R. & Shephard, E. A. Orphan receptor promiscuity in the induction of cytochromes p450 by xenobiotics. J. Biol. Chem. 276, 12822–12826 (2001).
Synold, T. W., Dussault, I. & Forman, B. M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7, 584–590 (2001).
Xie, W. et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev. 14, 3014–3023 (2000).
Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).
Poirier, J. et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc. Natl Acad. Sci. USA 92, 12260–12264 (1995).
Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl Acad. Sci. USA 97, 10613–10618 (2000).
Drazen, J. M. et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 22, 168–170 (1999).Shows that a promoter polymorphism regulates the expression of a drug target, and therefore drug effect.
Donger, C. et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96, 2778–2781 (1997).
Napolitano, C. et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J. Cardiovasc. Electrophysiol. 11, 691–696 (2000).
Yang, P. et al. Frequency of ion channel mutations and polymorphisms in a large population of patients with drug-associated Long QT Syndrome. Pacing Clin. Electrophys. 24, 579 (2001).
Wei, J. et al. KCNE1 polymorphism confers risk of drug-induced long QT syndrome by altering kinetic properties of IKs potassium channels. Circulation 100, 1–495 (1999).
Rigat, B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, 1343–1346 (1990).
Ueda, S., Meredith, P. A., Morton, J. J., Connell, J. M. & Elliott, H. L. ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans. Circulation 98, 2148–2153 (1998).
McNamara, D. M. et al. Pharmacogenetic interactions between β-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 103, 1644–1648 (2001).Variability in response to β-blocker therapy in heart failure due to a polymorphism in the ACE gene, the activity of which determines the biological context in which β-blockers act.
Vesell, E. S. & Page, J. G. Genetic control of drug levels in man: antipyrine. Science 161, 72–73 (1968).
Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).
Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).
Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).
Judson, R. & Stephens, J. C. Notes from the SNP vs haplotype front. Pharmacogenomics 2, 7–10 (2001).
Otterness, D. M., Szumlanski, C. L., Wood, T. C. & Weinshilboum, R. M. Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J. Clin. Invest. 101, 1036–1044 (1998).
McLeod, H. L., Krynetski, E. Y., Relling, M. V. & Evans, W. E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14, 567–572 (2000).The activity of thiopurine methyltransferase determines both the efficacy and the severe toxicity of drug therapy for the treatment of acute lymphoblastic leukaemia and, in some centres, genotyping to guide dosage is now routine; probably the first example of pre-prescription genotyping in clinical practice.
Rothstein, M. A. & Epps, P. G. Ethical and legal implications of pharmacogenomics. Nature Rev. Genet. 2, 228–231 (2001).
Robertson, J. A. Consent and privacy in pharmacogenetic testing. Nature Genet. 28, 207–209 (2001).Discusses the substantial ethical issues involved in genetic and, especially, in pharmacogenetic studies.
The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med. 325, 293–302 (1991).
Pfeffer, M. A. et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N. Engl. J. Med. 327, 669–677 (1992).
Brown, N. J., Ray, W. A., Snowden, M. & Griffin, M. R. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin. Pharmacol. Ther. 60, 8–13 (1996).
Brown, N. J., Snowden, M. & Griffin, M. R. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. J. Am. Med. Assoc. 278, 232–233 (1997).
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).
Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301–1307 (1995).
Ucar, M., Mjorndal, T. & Dahlqvist, R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf. 22, 441–457 (2000).
Kleyn, P. W. & Vesell, E. S. Genetic variation as a guide to drug development. Science 281, 1820–1821 (1998).
Mamiya, K. et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 39, 1317–1323 (1998).
Sullivan-Klose, T. H. et al. The role of the CYP2C9 Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6, 341–349 (1996).
Wedlund, P. J., Aslanian, W. S., McAllister, C. B., Wilkinson, G. R. & Branch, R. A. Mephenytoin hydroxylation deficiency in caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin. Pharmacol. Ther. 36, 773–780 (1984).
Dahl, M.-L., Johansson, I., Bertilsson, L., Ingelman-Sundberg, M. & Sjoeqvist, F. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J. Pharmacol. Exp. Ther. 274, 516–520 (1995).
Edeki, T. I., He, H. & Wood, A. J. Pharmacogenetic explanation for excessive β-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction. J. Am. Med. Assoc. 274, 1611–1613 (1995).
Zhou, H. H. & Wood, A. J. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin. Pharmacol. Ther. 57, 518–524 (1995).
Idle, J. R., Mahgoub, A., Lancaster, R. & Smith, R. L. Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sci. 22, 979–984 (1978).
Ellard, G. A., Mitchison, D. A., Girling, D. J., Nunn, A. J. & Fox, W. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. Am. Rev. Respir. Dis. 118, 628–629 (1978).
Stolk, J. N. et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 41, 1858–1866 (1998).
Israel, E. et al. The effect of polymorphisms of the β(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care Med. 162, 75–80 (2000).
Lutucuta, S., Ballantyne, C. M., Elghannam, H., Gotto, A. M. Jr, & Marian, A. J. Novel polymorphisms in promoter region of ATP binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. Circ. Res. 88, 969–973 (2001).
Kuivenhoven, J. A. et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N. Engl. J. Med. 338, 86–93 (1998).
Acknowledgements
Work in D.M.R.'s laboratory is supported in part by grants from the United States Public Health Service. D.M.R. holds the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi Corporation.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
glucose-6-phosphate dehydrogenase
FURTHER INFORMATION
Glossary
- ALKAPTONURIA
-
One of the earliest recognized “inborn errors of metabolism”, arising from the inheritance of two abnormal copies of the gene (recessive inheritance) that encodes homogentisic acid oxidase. The symptoms include arthritis and pigmented urine.
- PHENOTYPE
-
The clinical presentation or characteristics.
- ALLELES
-
Different versions of the same gene, one inherited from the mother and one from the father.
- NUCLEAR ORPHAN RECEPTOR
-
An analogue of a known nuclear receptor (often for a hormone) with no putative ligand yet identified.
- GENOTYPE
-
The genetic sequences that define the specific alleles that are present in an individual.
- QT INTERVAL
-
The QT interval represents the time for electrical activation and inactivation of the ventricles — the lower chambers of the heart. Prolongation of the QT interval can result in the potentially lethal arrhythmia known as Torsades de Pointes.
- HOMOZYGOUS
-
Two identical alleles at a gene or locus.
- MUTATION
-
A DNA variant that occurs rarely, and is often associated with disease.
- POLYMORPHISMS
-
Variants that are common (by definition greater than 1% of a given population), which can, in some cases, change an encoded amino acid, and have also been linked with altered gene function.
- POSITIONAL CLONING
-
An experimental technique to identify genes that contribute to a phenotype by first identifying the chromosomal locus (position). Positional cloning makes no assumptions as to underlying physiology, and so can identify genes with relationships to a specified phenotype that had not previously been suspected.
- HAPLOTYPE
-
The arrangement of individual alleles on a chromosome.
- NON-SYNONYMOUS CODING-REGION POLYMORPHISM
-
A DNA polymorphism in the coding region of a gene that results in a change in the encoded amino acid.
- SYNONYMOUS CODING-REGION POLYMORPHISM
-
A DNA polymorphism in the coding region of a gene that does not result in a change in the encoded amino acid.
- LINKAGE DISEQUILIBRIUM
-
The association between a pair of allelic variants that occurs more often than by chance.
- BONE MARROW APLASIA
-
Failure of the bone marrow to produce blood elements; a rare, unpredictable, and potentially fatal effect of some drugs.
- RHABDOMYOLYSIS
-
A syndrome of muscle damage that is sometimes provoked by drugs, which can cause fatal renal failure.
Rights and permissions
About this article
Cite this article
Roden, D., George Jr, A. The genetic basis of variability in drug responses. Nat Rev Drug Discov 1, 37–44 (2002). https://doi.org/10.1038/nrd705
Issue Date:
DOI: https://doi.org/10.1038/nrd705
This article is cited by
-
Pharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods
Nature Communications (2022)
-
Glutathione S-transferase M1 and T1 genes deletion polymorphisms and blood pressure control among treated essential hypertensive patients in Burkina Faso
BMC Research Notes (2021)
-
High Content Solid Dispersions for Dose Window Extension: A Basis for Design Flexibility in Fused Deposition Modelling
Pharmaceutical Research (2020)
-
Cardiovascular Risk Management and Hepatitis C: Combining Drugs
Clinical Pharmacokinetics (2019)
-
The GenomeAsia 100K Project enables genetic discoveries across Asia
Nature (2019)