Pharmacogenomics: A Clinician's Primer on Emerging Technologies for Improved Patient Care
2001; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês
10.4065/76.3.299
ISSN1942-5546
AutoresJames M. Rusnak, Robert M Kisabeth, David P. Herbert, Dennis M. McNeil,
Tópico(s)BRCA gene mutations in cancer
ResumoPharmacogenomics is a term recently coined to embody the concept of individualized and rational drug selection based on the genotype of a particular patient. Customization of drug therapy offers the potential for optimal safety and efficacy in an individual patient. Such a process contrasts current prescribing practices, which use medications shown to be safe and effective in patient populations or based on anecdotal experiences. Within patient populations, medications vary in their efficacy among individual patients. More importantly, a medication that is safe and effective in one patient may be ineffective or even harmful in another. Underlying many of these phenotypic differences are genotypic variants (polymorphisms) of key enzymes and proteins that affect the safety and efficacy of a drug in an individual patient. An understanding of these polymorphisms has the potential to enhance patient care by allowing physicians to customize the selection of medication to meet individual patient needs. Pharmacogenomics may also lead to improved compliance and shorter time to optimal disease management, thereby reducing morbidity and mortality. Significant cost savings could result from reductions in polypharmacy as well as from fewer physician encounters and hospitalizations for exacerbations of underlying illness and because of adverse drug reactions. Pharmacogenomics is a term recently coined to embody the concept of individualized and rational drug selection based on the genotype of a particular patient. Customization of drug therapy offers the potential for optimal safety and efficacy in an individual patient. Such a process contrasts current prescribing practices, which use medications shown to be safe and effective in patient populations or based on anecdotal experiences. Within patient populations, medications vary in their efficacy among individual patients. More importantly, a medication that is safe and effective in one patient may be ineffective or even harmful in another. Underlying many of these phenotypic differences are genotypic variants (polymorphisms) of key enzymes and proteins that affect the safety and efficacy of a drug in an individual patient. An understanding of these polymorphisms has the potential to enhance patient care by allowing physicians to customize the selection of medication to meet individual patient needs. Pharmacogenomics may also lead to improved compliance and shorter time to optimal disease management, thereby reducing morbidity and mortality. Significant cost savings could result from reductions in polypharmacy as well as from fewer physician encounters and hospitalizations for exacerbations of underlying illness and because of adverse drug reactions. In its broadest sense, pharmacogenomics represents the genetic basis of a drug's absorption (eg, active transport mechanisms), distribution (eg, plasma protein binding), metabolism (eg, cytochrome P-450 [CYP] metabolism), excretion (renal and biliary transport), and receptor-target affinity. Pharmacogenomics is an extension of the field of pharmacogenetics, which historically has investigated the metabolic fate of a drug based on individual genetic differences. Metabolism of drugs in vitro and in vivo occurs through phase 1 (oxidative) and phase 2 (conjugative) processes. The genetics of these metabolic pathways became apparent from a series of studies of twins conducted by Vesell and Page1Vesell ES Page JG Genetic control of drug levels in man: phenylbutazone.Science. 1968; 159: 1479-1480Crossref PubMed Scopus (120) Google Scholar, 2Vesell ES Page JG Genetic control of drug levels in man: antipyrine.Science. 1968; 161: 72-73Crossref PubMed Scopus (180) Google Scholar, 3Vesell ES Page JG Genetic control of dicumarol levels in man.J Clin Invest. 1968; 47: 2657-2663Crossref PubMed Scopus (117) Google Scholar in 1968. These studies showed that plasma half-lives of many drugs are remarkably similar in monozygotic twins, whereas wide variations in drug half-lives were seen among dizygotic twins, siblings, and the general population; these findings gave rise to the belief that interindividual variation in the efficacy and toxicity of drugs is largely determined by genetic factors. The recognition that a substance can be harmful in one person and safe in another, however, dates to the observation of Pythagoras in 510 BC that fava bean ingestion was dangerous for some people (now known to be those with glucose-6-phosphate dehydrogenase deficiency) but not for others. A landmark clinical observation by Gunn and Kalow clearly demonstrated the effect of pharmacogenetics on patient care.4Kalow W Familial incidence of low pseudocholinesterase level [letter].Lancet. 1956; 2: 576-577Abstract Scopus (104) Google Scholar, 5Kalow W Gunn DR The relationship between dose of succinylcholine and duration of apnea in man.J Pharmacol Exp Ther. 1957; 120: 203-214PubMed Google Scholar They observed prolonged effects of the neuromuscular blocking agent succinylcholine in certain patients undergoing electroconvulsive therapy. The greatly extended half-life of succinylcholine in these patients led to excessive neuromuscular blockade and prolonged apnea (succinylcholine-induced apnea), resulting in substantially reduced rates of drug metabolism due to an atypical pseudocholinesterase, hydrolyzing succinylcholine (and other substrates).6Kalow W Genest K A method for the detection of atypical forms of human serum cholinesterase: determination of dibucaine numbers.Can J Biochem Physiol (Ottawa). 1957; 35: 339-346Crossref PubMed Scopus (380) Google Scholar, 7Kalow W Staron N On distribution and inheritance of atypical forms of human serum cholinesterase as indicated by dibucaine numbers.Can J Biochem Physiol. 1957; 35: 1305-1320Crossref PubMed Scopus (166) Google Scholar Subsequent genetic studies have identified the normal human enzyme8Lockridge O Bartels CF Vaughan TA Wong CK Norton SE Johnson LL Complete amino acid sequence of human serum cholinesterase.J Biol Chem. 1987; 262: 549-557Abstract Full Text PDF PubMed Google Scholar and mutations responsible for expression of the atypical pseudocholinesterase,9McGuire MC Nogueira CP Bartels CF et al.Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase.Proc Natl Acad Sci U S A. 1989; 86: 953-957Crossref PubMed Scopus (168) Google Scholar and they have shown that succinylcholine-induced apnea is an autosomal recessive trait. Clinically important polymorphisms (stable genetic variations present in a population with ≥1% frequency) of other drug metabolism enzymes have also been identified. In vivo, N-acetyltransferase (NAT) 1 and 210Weber WW Hein DW N-acetylation pharmacogenetics.Pharmacol Rev. 1985; 37: 25-79PubMed Google Scholar act on many drugs, resulting in the transfer of an acetyl group from acetyl coenzyme A to target amines, producing an amide. This process increases the hydrophilicity of the drug and enhances its elimination. A polymorphism for NAT2 divides the general human population into rapid acetylators and slow acetylators. Because slow acetylators show decreases in enzyme activity, acetylation rates, and excretion of drugs metabolized by NAT2, higher plasma concentrations of these drugs (eg, dapsone, hydralazine, isoniazid) can be measured. Adverse drug reactions (ADRs) occur with increased frequency in slow acetylators, both directly (from elevated plasma concentrations of active drug) and indirectly (through production of alternate metabolites, typically produced only in minor quantities). In slow acetylators, isoniazid-induced vitamin B6 (pyridoxine) deficiency and resultant peripheral neuropathy are the first ADRs recognized to result from this polymorphism.11Lunde PK Frislid K Hansteen V Disease and acetylation polymorphism.Clin Pharmacokinet. 1977; 2: 182-197Crossref PubMed Scopus (120) Google Scholar The likelihood that a person will develop peripheral neuropathy and the degree of its severity are proportional to the total ingested dose of isoniazid and the patient's underlying nutritional status. These findings are the basis for the standard prescription of vitamin B6 (25–50 mg/d) as a concomitant medication for all patients undergoing isoniazid therapy. Conversely, polymorphisms that result in a fast-acetylator phenotype may increase the likelihood of an ADR to other drugs. For example, procainamide is metabolized to N-acetylprocainamide, which retains some antiarrhythmic activity and has a slower renal elimination rate. Consequently, a fast-acetylating patient is more vulnerable to an ADR related to procainamide, and this potential is magnified by the presence of underlying renal impairment. Most research in drug metabolism has focused on the CYP enzyme family. More than 40 CYP isozymes are present in humans, and their function is to metabolize exogenous pharmacologically or toxicologically active substances (xenobiotics) or to synthesize endogenous substances (such as steroid hormones). In humans, xenobiotics are principally metabolized by CYP 1, 2, and 3 (Table 1) and endogenous substances by CYP 1, 3, 4, 5, 7, 8, 11, 17, 19, 21, 24, 26, 27, 40, and 51. Athanassiadis et al19Athanassiadis D Cranston WI Juel-Jensen BE Oliver DO Clinical observations on the effects of debrisoquine sulphate in patients with high blood-pressure.BMJ. 1966; 2: 732-735Crossref PubMed Scopus (15) Google Scholar were the first to report a polymorphism of the CYP enzymes; CYP2D6, previously known as debrisoquin 4-hydroxylase, was discovered during clinical studies on debrisoquin, a sympatholytic antihypertensive agent. These investigators noted that patients possessing a CYP2D6 polymorphism required a lower dose for blood pressure control, and they showed low recovery of unmetabolized debrisoquin in their urine. Subsequent investigation showed that this discrepancy results from the extent to which debrisoquin is metabolized, not to such factors as absorption or renal clearance. More specifically, the ability to metabolize debrisoquin was bimodally distributed in family and controlled clinical studies; people could be identified readily as either extensive metabolizers or poor metabolizers, and the trait exhibited an autosomal recessive inheritance pattern.20Mahgoub A Idle JR Dring LG Lancaster R Smith RL Polymorphic hydroxylation of debrisoquine in man.Lancet. 1977; 2: 584-586Abstract PubMed Scopus (1018) Google Scholar Subsequently, sparteine and many other drugs (at present >50) have been shown to be metabolized by CYP2D6. Gene amplification has identified an autosomal dominant trait in a third subset of patients, ultraextensive metabolizers (UEMs),21Johansson I Lundqvist E Bertilsson L Dahl M-L Sjöqvist F Ingelman-Sundberg M Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine.Proc Natl Acad Sci U S A. 1993; 90: 11825-11829Crossref PubMed Scopus (629) Google Scholar in whom rates of drug metabolism are markedly increased and plasma levels of drugs metabolized by CYP2D6 are concomitantly lower. Standard doses of medications have been reported to result in increased rates of ADR in poor metabolizers and increased therapeutic failures in UEMs.22Balant-Gorgia AE Balant LP Garrone G High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data.Ther Drug Monit. 1989; 11: 415-420PubMed Google Scholar Identification of the CYP2D6 UEM genotype, however, has allowed for "rational megaprescribing" of medications to achieve therapeutic plasma drug concentrations and clinical responses in these patients.23Bertilsson L Dahl M-L Sjöqvist F et al.Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine [letter].Lancet. 1993; 341: 63Abstract PubMed Google ScholarTable 1Human Cytochrome P-450 Enzymes Involved With Xenobiotic Metabolism*An example of nomenclature for the cytochrome P-450 (CYP) isozymes: CYP2D6 is isoform 6 of subfamily D in the CYP2 family. Polymorphisms are identified by addition of a suffix (eg, CYP2D6*1 [wild type]; CYP2D6*2 [polymorphism]).12–18P-450Major isozymesGenotypic polymorphismSelected xenobiotics metabolized by the P-450 isozymeCYP1CYP1A1YesPolycyclic aromatic hydrocarbonsCYP1A2NoCaffeine, theophylline, imipramineCYP2CYP2A6YesNicotineCYP2C9YesPhenytoin, warfarin, nonsteroidal anti-inflammatory drugsCYP2C19YesAmitriptyline, diazepam, omeprazole, proguanil, hexobarbital, propranolol, imipramineCYP2D6YesAmitriptyline, imipramine, nortriptyline, amiodarone, flecainide, propafenone, metoprolol, propranolol, perphenazine, thioridazine, codeine, haloperidol, procainamide, venlafaxineCYP2E1YesEthanolCYP3CYP3A4NoAmitriptyline, clarithromycin, cyclosporine, erythromycin, tacrolimus, lidocaine, nifedipine, tamoxifen* An example of nomenclature for the cytochrome P-450 (CYP) isozymes: CYP2D6 is isoform 6 of subfamily D in the CYP2 family. Polymorphisms are identified by addition of a suffix (eg, CYP2D6*1 [wild type]; CYP2D6*2 [polymorphism]).12Lin KM Poland RE Wan YJ Smith MW Lesser IM The evolving science of pharmacogenetics: clinical and ethnic perspectives.Psychopharmacol Bull. 1996; 32: 205-217PubMed Google Scholar, 13Linder MW Prough RA Valdes Jr, R Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency.Clin Chem. 1997; 43: 254-266PubMed Google Scholar, 14Meyer UA Zanger UM Molecular mechanisms of genetic polymorphisms of drug metabolism.Annu Rev Pharmacol Toxicol. 1997; 37: 269-296Crossref PubMed Scopus (492) Google Scholar, 15Hasler JA Estabrook R Murray M et al.Pharmacogenetics of cytochromes P450.Mol Aspects Med. 1999; 20: 12-137Crossref PubMed Scopus (151) Google Scholar, 16Evans WE Relling MV Pharmacogenomics: translating functional genomics into rational therapeutics.Science. 1999; 286: 487-491Crossref PubMed Scopus (2128) Google Scholar, 17Lessard É Hamelin BA Labbé L O'Hara G Bélanger PM Turgeon J Involvement of CYP2D6 activity in the N-oxidation of procainamide in man.Pharmacogenetics. 1999; 9: 683-696Crossref PubMed Google Scholar, 18Lessard É Yessine MA Hamelin BA O'Hara G LeBlanc J Turgeon J Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans.Pharmacogenetics. 1999; 9: 435-443Crossref PubMed Google Scholar Open table in a new tab Polymorphisms related to drug metabolism represent an important element of a patient's clinical response and adverse events related to pharmacotherapy (Table 2). Adverse drug reactions are a major cause of patient morbidity and mortality. In a recent meta-analysis of ADRs, Lazarou et al48Lazarou J Pomeranz BH Corey PN Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.JAMA. 1998; 279: 1200-1205Crossref PubMed Scopus (4123) Google Scholar reported that the overall incidence of serious or fatal ADRs in hospitalized patients in the United States is 6.7% and 0.32%, respectively, estimating 2,216,000 serious ADRs and 106,000 fatal ADRs during 1994 alone. Many of these ADRs were undoubtedly a result of genotypic-dependent drug reactions.Table 2Selected Examples of Clinically Important Polymorphisms*ACE = angiotensin-converting enzyme; AE = adverse effect; APOE = apolipoprotein E; CYP = cytochrome P-450; eNOS = endothelial nitric oxide synthetase; G6PD = glucose-6-phosphate dehydrogenase; GST = glutathione S-transferase; 5-HT2A = serotonin 2A receptor; 5-HTT = serotonin transporter; NAT = N-acetyltransferase; PM = poor metabolizer; TCAs = tricyclic antidepressants; TPMT = thiopurine methyltransferase; UEM = ultraextensive metabolizer; UGT1A1 = uridine 5′-diphosphate glucuronosyltransferase 1A1 (Gilbert syndrome, autosomal dominant reduction in gene expression secondary to additional TA repeat in TATA box of UGT1A1 promoter47).PolymorphismDrugReported clinical outcomeReferencesMetabolismPhase 1 (oxidation) enzymes CYP2C9WarfarinStable dose requirement, bleeding risks24Aithal GP Day CP Kesteven PJ Daly AK Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.Lancet. 1999; 353: 717-719Abstract Full Text Full Text PDF PubMed Scopus (1173) Google Scholar CYP2C19 (PM)OmeprazoleGastric pH, Helicobacter pylori and ulcer cure rates25Furuta T Ohashi K Kamata T et al.Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.Ann Intern Med. 1998; 129: 1027-1030Crossref PubMed Scopus (339) Google Scholar, 26Furuta T Ohashi K Kosuge K et al.CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans.Clin Pharmacol Ther. 1999; 65: 552-561Crossref PubMed Scopus (290) Google ScholarProguanilEfficacy of malaria prophylaxis27Helsby NA Ward SA Howells RE Breckenridge AM In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme.Br J Clin Pharmacol. 1990; 30: 287-291Crossref PubMed Scopus (66) Google Scholar, 28Ward SA Helsby NA Skjelbo E Brosen K Gram LF Breckenbridge AM The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism—a panel study.Br J Clin Pharmacol. 1991; 31: 689-692Crossref PubMed Scopus (166) Google Scholar CYP2D6 (PM)CodeineInadequate pain management29Sindrup SH Brosen K The pharmacogenetics of codeine hypoalgesia.Pharmacogenetics. 1995; 5: 335-346Crossref PubMed Scopus (192) Google ScholarTCAsIncreased adverse effects, increased cardiotoxicity risk12Lin KM Poland RE Wan YJ Smith MW Lesser IM The evolving science of pharmacogenetics: clinical and ethnic perspectives.Psychopharmacol Bull. 1996; 32: 205-217PubMed Google Scholar, 22Balant-Gorgia AE Balant LP Garrone G High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data.Ther Drug Monit. 1989; 11: 415-420PubMed Google Scholar, 30Bluhm RE Wilkinson GR Shelton R Branch RA Genetically determined drug-metabolizing activity and desipramine-associated cardiotoxicity: a case report.Clin Pharmacol Ther. 1993; 53: 89-95Crossref PubMed Scopus (34) Google ScholarVenlafaxineCardiovascular adverse events18Lessard É Yessine MA Hamelin BA O'Hara G LeBlanc J Turgeon J Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans.Pharmacogenetics. 1999; 9: 435-443Crossref PubMed Google Scholar CYP2D6 (UEM)TCAsEfficacy (nonresponder)22Balant-Gorgia AE Balant LP Garrone G High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data.Ther Drug Monit. 1989; 11: 415-420PubMed Google Scholar, 23Bertilsson L Dahl M-L Sjöqvist F et al.Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine [letter].Lancet. 1993; 341: 63Abstract PubMed Google Scholar Dihydropyrimidine dehydrogenaseFluorouracilNeurotoxicity31Diasio RB Clinical implications of dihydropyrimidine dehydrogenase inhibition.Oncology (Huntingt). 1999; 13: 17-21PubMed Google ScholarPhase 2 (conjugation) enzymes Atypical pseudocholinesteraseSuccinylcholineSuccinylcholine-induced apnea5Kalow W Gunn DR The relationship between dose of succinylcholine and duration of apnea in man.J Pharmacol Exp Ther. 1957; 120: 203-214PubMed Google Scholar, 9McGuire MC Nogueira CP Bartels CF et al.Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase.Proc Natl Acad Sci U S A. 1989; 86: 953-957Crossref PubMed Scopus (168) Google Scholar NAT2 (slow acetylator)IsoniazidPeripheral neuropathy11Lunde PK Frislid K Hansteen V Disease and acetylation polymorphism.Clin Pharmacokinet. 1977; 2: 182-197Crossref PubMed Scopus (120) Google ScholarHydralazineRisk of drug-induced lupus, hypotension32Perry Jr, HM Tan EM Carmody S Sakamoto A Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine.J Lab Clin Med. 1970; 76: 114-125PubMed Google Scholar UGT1A1IrinotecanSevere neutropenia, chemotherapeutic AE33Wasserman E Myara A Lokiec F et al.Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.Ann Oncol. 1997; 8: 1049-1051Crossref PubMed Scopus (206) Google Scholar GSTD-penicillamineEfficacy in rheumatoid arthritis34Layton MA Jones PW Alldersea JE et al.The therapeutic response to D-penicillamine in rheumatoid arthritis: influence of glutathione S-transferase polymorphisms.Rheumatology (Oxford). 1999; 38: 43-47Crossref PubMed Scopus (20) Google Scholar TPMTAzathioprine, mercaptopurineLeukopenia, death35Evans WE Horner M Chu YQ Kalwinsky D Roberts WM Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia.J Pediatr. 1991; 119: 985-989Abstract Full Text PDF PubMed Scopus (375) Google Scholar, 36McLeod HL Miller DR Evans WE Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient [letter].Lancet. 1993; 341: 1151Abstract PubMed Scopus (117) Google ScholarReceptors or drug targets ACECaptopril, enalaprilHypertension and antiproteinuric effects37Haas M Yilmaz N Schmidt A Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease et al.Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease.Kidney Blood Press Res. 1998; 21: 66-69Crossref PubMed Scopus (61) Google Scholar, 38Parving HH Jacobsen P Tarnow L et al.Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.BMJ. 1996; 313: 591-594Crossref PubMed Scopus (192) Google Scholar, 39Penno G Chaturvedi N Talmud PJ et al.Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial: EURODIAB Controlled Trial of Lisinopril in IDDM.Diabetes. 1998; 47: 1507-1511Crossref PubMed Scopus (136) Google Scholar β2-adrenergic receptorAlbuterolAirway responsiveness to albuterol40Lima JJ Thomason DB Mohamed MH Eberle LV Self TH Johnson JA Impact of genetic polymorphisms of the 2-adrenergic receptor on albuterol bronchodilator pharmacodynamics.Clin Pharmacol Ther. 1999; 65: 519-525Crossref PubMed Scopus (247) Google Scholar 5-HT2AClozapineEfficacy in patients with schizophrenia41Arranz MJ Collier DA Munro J et al.Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine.Neurosci Lett. 1996; 217: 177-178Crossref PubMed Scopus (117) Google ScholarOther P-glycoproteinDigoxinDrug absorption, plasma concentration42Hoffmeyer S Burk O von Richter O 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 U S A. 2000; 97: 3473-3478Crossref PubMed Scopus (2344) Google Scholar G6PDManyHemolytic anemia43Beutler E G6PD deficiency.Blood. 1994; 84: 3613-3636Crossref PubMed Google Scholar APOE ɛ4TacrinePoor response in Alzheimer disease44Poirier J Delisle MC Quirion R et al.Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.Proc Natl Acad Sci U S A. 1995; 92: 12260-12264Crossref PubMed Scopus (567) Google Scholar 5-HTTFluvoxamineEfficacy in delusional depression45Smeraldi E Zanardi R Benedetti F Di Bella D Perez J Catalano M Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine.Mol Psychiatry. 1998; 3: 508-511Crossref PubMed Scopus (590) Google Scholar eNOSPhenylephrineVascular tone46Philip I Plantefeve G Vuillaumier-Barrot S et al.G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine.Circulation. 1999; 99: 3096-3098Crossref PubMed Scopus (171) Google Scholar* ACE = angiotensin-converting enzyme; AE = adverse effect; APOE = apolipoprotein E; CYP = cytochrome P-450; eNOS = endothelial nitric oxide synthetase; G6PD = glucose-6-phosphate dehydrogenase; GST = glutathione S-transferase; 5-HT2A = serotonin 2A receptor; 5-HTT = serotonin transporter; NAT = N-acetyltransferase; PM = poor metabolizer; TCAs = tricyclic antidepressants; TPMT = thiopurine methyltransferase; UEM = ultraextensive metabolizer; UGT1A1 = uridine 5′-diphosphate glucuronosyltransferase 1A1 (Gilbert syndrome, autosomal dominant reduction in gene expression secondary to additional TA repeat in TATA box of UGT1A1 promoter47Hall D Ybazeta G Destro-Bisol G Petzl-Erler ML Di Rienzo A Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates.Pharmacogenetics. 1999; 9: 591-599Crossref PubMed Scopus (133) Google Scholar). Open table in a new tab Investigators at some medical facilities routinely perform phenotyping or genotyping of a few selected enzymes before initiation of specific types of drug therapy, seeking to individualize therapy to improve the safety or efficacy. For example, thiopurine methyltransferase (TPMT) is a genetic polymorphism that significantly affects the safety of certain drug therapies. Approximately 90% of white people and African Americans have high activity of the enzyme, 10% show intermediate activity, and 1 in 300 is TPMT deficient.49Weinshilboum RM Sladek SL Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.Am J Hum Genet. 1980; 32: 651-662PubMed Google Scholar, 50Van Loon JA Weinshilboum RM Thiopurine methyltransferase biochemical genetics: human lymphocyte activity.Biochem Genet. 1982; 20: 637-658Crossref PubMed Scopus (86) Google Scholar, 51Szumlanski CL Honchel R Scott MC Weinshilboum RM Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes.Pharmacogenetics. 1992; 2: 148-159Crossref PubMed Scopus (186) Google Scholar No phenotype is apparent until the patient is treated with azathioprine, mercaptopurine, or thioguanine (for various autoimmune, dermatologic, hematologic, or gastrointestinal disorders), after which TPMT-deficient patients develop potentially fatal leukopenia. Emerging evidence also suggests that heterozygous persons have a higher frequency of hepatic failure and other adverse effects.52Alves S Prata MJ Ferreira F Amorim A Thiopurine methyltransferase pharmacogenetics: alternative molecular diagnosis and preliminary data from Northern Portugal.Pharmacogenetics. 1999; 9: 257-261PubMed Google Scholar, 53Krynetski EY Evans WE Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm.Pharm Res. 1999; 16: 342-349Crossref PubMed Scopus (135) Google Scholar Identification of TPMT deficiency by genetic methods or enzyme activity levels before initiation of drug therapy allows administration of an individualized dose (10%-15% of the conventional dose) that is both safe and effective.53Krynetski EY Evans WE Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm.Pharm Res. 1999; 16: 342-349Crossref PubMed Scopus (135) Google Scholar Drug metabolism pharmacogenomics has a role not only in drug safety but also in drug efficacy. In a Japanese cohort of patients with peptic ulcer disease and Helicobacter pylori infection, Furuta et al25Furuta T Ohashi K Kamata T et al.Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.Ann Intern Med. 1998; 129: 1027-1030Crossref PubMed Scopus (339) Google Scholar reported dramatically different cure rates with omeprazole and amoxicillin in patients with polymorphisms of CYP2C19:28.6%, 60%, and 100% for the rapid-, intermediate-, and poor-metabolizer groups, respectively. Omeprazole is metabolized by CYP2C19, and the slow metabolism in the poor-metabolizer group is thought to contribute to the greater efficacy in these patients. In support of that theory, other studies have demonstrated higher plasma omeprazole levels and higher intragastric pH in CYP2C19 poor metabolizers.26Furuta T Ohashi K Kosuge K et al.CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans.Clin Pharmacol Ther. 1999; 65: 552-561Crossref PubMed Scopus (290) Google Scholar Furthermore, clarithromycin, an antibiotic used frequently in combination regimens for H pylori eradication, is also metabolized by CYP2C19. Recent studies comparing the efficacy of H pylori treatment regimens with and without clarithromycin (omeprazole, amoxicillin, and clarithromycin vs omeprazole and amoxicillin with or without sucralfate) have shown that CYP2C19 poor metabolizers (m2/m2 genotype) have a 100% cure rate with either regimen, that cure rates for CYP2C19 rapid metabolizers (m1/m1 genotype) and intermediate metabolizers (m1/m2 genotype) are significantly improved by the addition of clarithromycin, and that clarithromycin increases the plasma concentration of omeprazole.54Tanigawara Y Aoyama N Kita T et al.CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori.Clin Pharmacol Ther. 1999; 66: 528-534Crossref PubMed Google Scholar, 55Aoyama N Tanigawara Y Kita T et al.Sufficient
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