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Role of Pharmacogenomics in Reducing the Risk of Drug-Related Iatrogenesis

  • Clinical Pharmacology (L Brunetti, Section Editor)
  • Published:
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Abstract

Purpose of Review

Drug-related iatrogenesis includes medication errors, adverse drug events, and adverse drug reactions and is among the most prevalent causes of death in the USA. Accessibility of pharmacogenetic testing and better understanding of mechanisms associated with drug-related iatrogenesis offer clinicians greater opportunities to establish tailored and precise pharmacological treatments to improve efficacy and decrease the risk of drug-related severe side effects.

Recent Findings

Three conditions associated with drug-related iatrogenesis that could be prevented by pre-emptive pharmacogenomic testing are discussed with three relevant drug examples for each condition. Conditions discussed are (1) N-acetyltransferase (NAT) polymorphisms, N-oxidation, and drug-related toxicity; (2) glucose-6-phosphate dehydrogenase (G6PD) and drug-related toxicity; and (3) HLA and drug-related hypersensitivity. The three specific drugs discussed under these conditions are (1) for NAT, isoniazid, hydralazine, and procainamide; (2) for G6PD, primaquine, rasburicase, and nitrofurantoin; and (3) for HLA, abacavir, carbamazepine, and allopurinol.

Summary

Detailed information is presented and supported by an exhaustive literature search. An introduction to each condition is provided to review the most important elements associated with the drug-related iatrogenic condition. In each case, a summary of drug action and metabolism, whenever relevant, is presented. The inter-relationship between the associated conditions with each drug is described in detail with a special attention given to the genetic component of this drug-related iatrogenic condition. Comments are provided by the authors at the end of each subsection on the value of pharmacogenomic testing to prevent drug-related iatrogenic events.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Molière PJ. Le malade imaginaire. Act III,1673. http://clicnet.swarthmore.edu/litterature/classique/moliere/mi/mi.introduction.html.

  2. Leelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: a systematic review and meta-analysis. J Am Pharm Assoc: JAPhA. 2017;576(6):729-38.e10. https://doi.org/10.1016/j.japh.2017.06.002.

    Article  Google Scholar 

  3. •• Ratigan AR, Michaud V, Turgeon J, Bikmetov R, Gaona Villarreal G, Anderson HD, et al. Longitudinal association of a medication risk score with mortality among ambulatory patients acquired through electronic health record data. J Patient Saf. 2021;17(4):249–55. https://doi.org/10.1097/pts.0000000000000829. (This article reported findings from a longitudinal study in a Patient Safety Organization which found that the Medwise™ Risk Score was independently associated with death.)

    Article  PubMed  PubMed Central  Google Scholar 

  4. 2016. https://basicmedicalkey.com/medication-misadventures-i-adverse-drug-reactions/. Accessed August 25, 2021.

  5. VA Center for Medication Safety and VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel, online. 2006. https://www.pbm.va.gov/PBM/vacenterformedicationsafety/tools/AdverseDrugReaction.pdf. Accessed August 25, 2021.

  6. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician’s guide to terminology, documentation, and reporting. Ann Intern Med. 2004;140(10):795–801. https://doi.org/10.7326/0003-4819-140-10-200405180-00009.

    Article  PubMed  Google Scholar 

  7. WHO. International drug monitoring : the role of national centres, report of a WHO meeting [held in Geneva from 20 to 25 September 1971]. 1972. p. 47.

  8. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9. https://doi.org/10.1016/s0140-6736(00)02799-9.

    Article  CAS  PubMed  Google Scholar 

  9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45. https://doi.org/10.1038/clpt.1981.154.

    Article  CAS  PubMed  Google Scholar 

  10. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. Jama. 1979;242(7):623-32.

  11. Cicali BMV, Knowlton CH, Turgeon J. Application of a Novel Medication-Related Risk Stratification Strategy for a Self-Funded Employer Population. Benefits Q. 2018;34(2):49–55.

    Google Scholar 

  12. Bankes DL, Jin H, Finnel S, Michaud V, Knowlton CH, Turgeon J, et al. Association of a Novel Medication Risk Score with Adverse Drug Events and Other Pertinent Outcomes Among Participants of the Programs of All-Inclusive Care for the Elderly. Pharmacy (Basel). 2020;8(2). https://doi.org/10.3390/pharmacy8020087.

  13. •• Michaud V, Smith MK, Bikmetov R, Dow P, Johnson J, Stein A, et al. Association of the MedWise Risk Score with health care outcomes. Am J Manag Care. 2021;27(16 Suppl):S280-s91. https://doi.org/10.37765/ajmc.2021.88753.T. (This article reported findings from a study in an Enhanced Medication Therapy Management setting and found that the MedWise™ Risk Score was associated with adverse health outcomes, including ADEs, falls, and death.)

    Article  PubMed  Google Scholar 

  14. •• SanFilippo S, Michaud V, Wei J, Bikmetov R, Turgeon J, Brunetti L. Classification and Assessment of Medication Risk in the Elderly (CARE): Use of a Medication Risk Score to Inform Patients’ Readmission Likelihood after Hospital Discharge. Journal of Clinical Medicine. 2021;10(17):3947. (This article reported findings from a study demonstrating that the MedWise™ Risk Score was associated with readmission in patients discharged to home.)

  15. Michaud V, Turgeon J. Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy. Pharmaceutics. 2021;13(2). https://doi.org/10.3390/pharmaceutics13020197.

  16. Pharmacogenetics WK. heredity and the response to drugs. Philadelphia, Pennsylvania: S.B. Saunders Co.; 1962.

    Google Scholar 

  17. The Wall Street Journal, online. 1999. https://www.wsj.com/articles/SB924225073307249185. Accessed August 25, 2021.

  18. The International Human Genome Sequencing Consortium, Online. 2012. https://www.genome.gov/11006929/2003-release-international-consortium-completes-hgp. Accessed January 14, 2021.

  19. International Human Genome Sequencing C. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931-45 https://doi.org/10.1038/nature03001.

  20. Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmacogenetic-guided treatment: are we there yet? Pharmacogenomics J. 2017;17(5):395–402. https://doi.org/10.1038/tpj.2017.21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. • Bain KT, Knowlton CH, Matos A. Cost avoidance related to a pharmacist-led pharmacogenomics service for the Program of All-inclusive Care for the Elderly. Pharmacogenomics. 2020;21(10):651–61. https://doi.org/10.2217/pgs-2019-0197. (This article reported findings demonstrating the efficiency of pharmacogenomic testing in reducing costs.)

    Article  CAS  PubMed  Google Scholar 

  22. Bain KT, Matos A, Knowlton CH, McGain D. Genetic variants and interactions from a pharmacist-led pharmacogenomics service for PACE. Pharmacogenomics. 2019;20(10):709–18. https://doi.org/10.2217/pgs-2019-0047.

    Article  CAS  PubMed  Google Scholar 

  23. Leopold JA, Loscalzo J. Emerging Role of Precision Medicine in Cardiovascular Disease. Circ Res. 2018;122(9):1302–15. https://doi.org/10.1161/circresaha.117.310782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bradley P, Shiekh M, Mehra V, Vrbicky K, Layle S, Olson MC, et al. Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility. J Psychiatr Res. 2018;96:100–7. https://doi.org/10.1016/j.jpsychires.2017.09.024.

    Article  PubMed  Google Scholar 

  25. Schwartz EJ, Turgeon J, Patel J, Patel P, Shah H, Issa AM, et al. Implementation of a Standardized Medication Therapy Management Plus Approach within Primary Care. J Am Board Fam Med. 2017;30(6):701–14. https://doi.org/10.3122/jabfm.2017.06.170145.

    Article  PubMed  Google Scholar 

  26. Bain KT, McGain D, Cicali EJ, Knowlton CH, Michaud V, Turgeon J. Precision medication: An illustrative case series guiding the clinical application of multi-drug interactions and pharmacogenomics. Clin Case Rep. 2020;8(2):305–12. https://doi.org/10.1002/ccr3.2604.

    Article  PubMed  Google Scholar 

  27. Deodhar MDP, Al Rihani SB, Turgeon J, Michaud V. An illustrative case of phenoconversion due to multi-drug interactions. Clin Case Rep J. 2020;1(3):1–6.

    Google Scholar 

  28. Shojaat S BC, Turgeon J, Amin N. Medication-related problems in older adults and the importance of comprehensive medication. Clin Case Rep. 2020;10(8).

  29. Ballinghoff TBK, Matos A, Bardolia C, Turgeon J, Amin NS. Opioid response in an individual with altered cytochrome P450 2D6 activity: implications of a pharmacogenomics case. Clin Case Rep J. 2020;1(6):1–4.

    Google Scholar 

  30. Dawson N, Bain K, Mesman J. Comparing two measures of maternal sensitivity: goodness of fit with a South African cultural context. Attach Hum Dev. 2018:1-9. https://doi.org/10.1080/14616734.2018.1454056.

  31. Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev. 2000;9(1):29–42.

    CAS  PubMed  Google Scholar 

  32. Klaassen CD, Amdur, M O, Doull J. . Casarett and Doull’s toxicology; The basic science of poisons, 5th ed. 5th ed. New York: McGraw-Hill; 1996.

  33. Grant DM, Hughes NC, Janezic SA, Goodfellow GH, Chen HJ, Gaedigk A, et al. Human acetyltransferase polymorphisms. Mutat Res. 1997;376(1–2):61–70. https://doi.org/10.1016/s0027-5107(97)00026-2.

    Article  CAS  PubMed  Google Scholar 

  34. Boukouvala S, Price N, Sim E. Identification and functional characterization of novel polymorphisms associated with the genes for arylamine N-acetyltransferases in mice. Pharmacogenetics. 2002;12(5):385–94. https://doi.org/10.1097/00008571-200207000-00006.

    Article  CAS  PubMed  Google Scholar 

  35. Jennne JW. Partial purification and properties of the isoniazid transacetylase in human liver. Its relationship to the acetylation of p-aminosalicylic acid. J Clin Invest. 1965;44(12):1992–2002. https://doi.org/10.1172/jci105306.

  36. Grant DM, Blum M, Beer M, Meyer UA. Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Mol Pharmacol. 1991;39(2):184–91.

    CAS  PubMed  Google Scholar 

  37. Hughes HB, Biehl JP, Jones AP, Schmidt LH. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am Rev Tuberc. 1954;70(2):266–73. https://doi.org/10.1164/art.1954.70.2.266.

    Article  CAS  PubMed  Google Scholar 

  38. Blum M, Demierre A, Grant DM, Heim M, Meyer UA. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci U S A. 1991;88(12):5237–41. https://doi.org/10.1073/pnas.88.12.5237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vatsis KP, Martell KJ, Weber WW. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc Natl Acad Sci U S A. 1991;88(14):6333–7. https://doi.org/10.1073/pnas.88.14.6333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Blum M, Grant DM, McBride W, Heim M, Meyer UA. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 1990;9(3):193–203. https://doi.org/10.1089/dna.1990.9.193.

    Article  CAS  PubMed  Google Scholar 

  41. Hickman D, Risch A, Buckle V, Spurr NK, Jeremiah SJ, McCarthy A, et al. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem J. 1994;297(Pt 3):441–5. https://doi.org/10.1042/bj2970441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Democritus University of Thrace, Online. 2016. http://nat.mbg.duth.gr/. Accessed August 25, 2021

  43. Hein DW, Boukouvala S, Grant DM, Minchin RF, Sim E. Changes in consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenet Genomics. 2008;18(4):367–8. https://doi.org/10.1097/FPC.0b013e3282f60db0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McDonagh EM, Boukouvala S, Aklillu E, Hein DW, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenet Genomics. 2014;24(8):409–25. https://doi.org/10.1097/fpc.0000000000000062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity. J Toxicol Environ Health B Crit Rev. 2009;12(5–6):440–72. https://doi.org/10.1080/10937400903158383.

    Article  CAS  PubMed  Google Scholar 

  46. • Wichukchinda N, Pakdee J, Kunhapan P, Imunchot W, Toyo-Oka L, Tokunaga K, et al. Haplotype-specific PCR for NAT2 diplotyping. Hum Genome Var. 2020;7:13. https://doi.org/10.1038/s41439-020-0101-7. (This novel HS-PCR method allows direct NAT2 diplotyping, enabling the implementation of NAT2 acetylator phenotypes in clinical pharmacogenetic testing.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tilak AV, Iyer SN, Mukherjee MS, Singhal RS, Lele SS. Full-gene-sequencing analysis of N-acetyltransferase-2 in an adult Indian population. Genet Test Mol Biomarkers. 2013;17(3):188–94. https://doi.org/10.1089/gtmb.2012.0258.

    Article  CAS  PubMed  Google Scholar 

  48. National Institutes of Health, online. 2021. https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=NAT2. Accessed August 26, 2021.

  49. •• Yoo H, Chun Ji S, Cho J-Y, Kim S-H, Yoon JG, Goo Lee M, et al. A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators. Pharmacogenetics Genomics. 2021;31(3):68–73. https://doi.org/10.1097/fpc.0000000000000423. (This study demonstrates that NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.)

    Article  CAS  PubMed  Google Scholar 

  50. Azuma J, Ohno M, Kubota R, Yokota S, Nagai T, Tsuyuguchi K, et al. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. Eur J Clin Pharmacol. 2013;69(5):1091–101. https://doi.org/10.1007/s00228-012-1429-9.

    Article  CAS  PubMed  Google Scholar 

  51. Centers for Disease Control and Prevention, online. 2016. https://www.cdc.gov/tb/topic/treatment/tbdisease.htm. Accessed August 26, 2021.

  52. Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WC, van der Ven AJ, Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol. 2008;23(2):192–202. https://doi.org/10.1111/j.1440-1746.2007.05207.x.

    Article  CAS  PubMed  Google Scholar 

  53. Preziosi P. Isoniazid: metabolic aspects and toxicological correlates. Curr Drug Metab. 2007;8(8):839–51. https://doi.org/10.2174/138920007782798216.

    Article  CAS  PubMed  Google Scholar 

  54. Metushi IG, Cai P, Zhu X, Nakagawa T, Uetrecht JP. A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clin Pharmacol Ther. 2011;89(6):911–4. https://doi.org/10.1038/clpt.2010.355.

    Article  CAS  PubMed  Google Scholar 

  55. Mahapatra S, Woolhiser LK, Lenaerts AJ, Johnson JL, Eisenach KD, Joloba ML, et al. A novel metabolite of antituberculosis therapy demonstrates host activation of isoniazid and formation of the isoniazid-NAD+ adduct. Antimicrob Agents Chemother. 2012;56(1):28–35. https://doi.org/10.1128/aac.05486-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Drug Metab Rev. 2012;44(1):116–26. https://doi.org/10.3109/03602532.2011.605790.

    Article  CAS  PubMed  Google Scholar 

  57. Fukino K, Sasaki Y, Hirai S, Nakamura T, Hashimoto M, Yamagishi F, et al. Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci. 2008;33(2):187–95. https://doi.org/10.2131/jts.33.187.

    Article  CAS  PubMed  Google Scholar 

  58. Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites. Clin Pharmacol Ther. 1975;18(1):70–9. https://doi.org/10.1002/cpt197518170.

    Article  CAS  PubMed  Google Scholar 

  59. Ungcharoen U, Sriplung H, Mahasirimongkol S, Chusri S, Wichukchinda N, Mokmued P, et al. The Influence of NAT2 Genotypes on Isoniazid Plasma Concentration of Pulmonary Tuberculosis Patients in Southern Thailand. Tuberc Respir Dis (Seoul). 2020;83(Supple 1):S55–s62. https://doi.org/10.4046/trd.2020.0068.

  60. • Lee M-R, Huang H-L, Lin S-W, Cheng M-H, Lin Y-T, Chang S-Y, et al. Isoniazid Concentration and NAT2 Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI. Journal of Clinical Medicine. 2019;8(6):812.. (This study demonstrated that NAT2 genotype and isoniazid levels, as part of a cocktail with rifapentine, were associated with systemic drug reactions.)

  61. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–52. https://doi.org/10.1164/rccm.200510-1666ST.

    Article  CAS  PubMed  Google Scholar 

  62. Zabost A, Brzezińska S, Kozińska M, Błachnio M, Jagodziński J, Zwolska Z, et al. Correlation of N-acetyltransferase 2 genotype with isoniazid acetylation in Polish tuberculosis patients. Biomed Res Int. 2013;2013:853602. https://doi.org/10.1155/2013/853602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eisenhut M, Thieme D, Schmid D, Fieseler S, Sachs H. Hair Analysis for Determination of Isoniazid Concentrations and Acetylator Phenotype during Antituberculous Treatment. Tuberc Res Treat. 2012;2012:327027. https://doi.org/10.1155/2012/327027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kiser JJ, Zhu R, DʼArgenio DZ, Cotton MF, Bobat R, McSherry GD, et al. Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants. Ther Drug Monit. 2012;34(4):446–51. https://doi.org/10.1097/FTD.0b013e31825c4bc3.

  65. Bekker A, Schaaf HS, Seifart HI, Draper HR, Werely CJ, Cotton MF, et al. Pharmacokinetics of isoniazid in low-birth-weight and premature infants. Antimicrob Agents Chemother. 2014;58(4):2229–34. https://doi.org/10.1128/aac.01532-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. •• Khan S, Mandal RK, Elasbali AM, Dar SA, Jawed A, Wahid M, et al. Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence. Biosci Rep. 2019;39(1). https://doi.org/10.1042/bsr20180845.

  67. Possuelo LG, Castelan JA, de Brito TC, Ribeiro AW, Cafrune PI, Picon PD, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol. 2008;64(7):673–81. https://doi.org/10.1007/s00228-008-0484-8.

    Article  CAS  PubMed  Google Scholar 

  68. Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb). 2007;87(6):551–6. https://doi.org/10.1016/j.tube.2007.05.012.

    Article  CAS  PubMed  Google Scholar 

  69. Lee SW, Chung LS, Huang HH, Chuang TY, Liou YH, Wu LS. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis. 2010;14(5):622–6.

    PubMed  Google Scholar 

  70. Teixeira RL, Morato RG, Cabello PH, Muniz LM, Moreira Ada S, Kritski AL, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients. Mem Inst Oswaldo Cruz. 2011;106(6):716–24. https://doi.org/10.1590/s0074-02762011000600011.

    Article  CAS  PubMed  Google Scholar 

  71. Chamorro JG, Castagnino JP, Musella RM, Nogueras M, Aranda FM, Frías A, et al. Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs. J Gastroenterol Hepatol. 2013;28(2):323–8. https://doi.org/10.1111/jgh.12069.

    Article  CAS  PubMed  Google Scholar 

  72. Rana SV, Ola RP, Sharma SK, Arora SK, Sinha SK, Pandhi P, et al. Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatol Int. 2012;6(1):397–402. https://doi.org/10.1007/s12072-011-9309-4.

    Article  CAS  PubMed  Google Scholar 

  73. Khalili H, Fouladdel S, Sistanizad M, Hajiabdolbaghi M, Azizi E. Association of N-acetyltransferase-2 genotypes and anti-tuberculosis induced liver injury; first case-controlled study from Iran. Curr Drug Saf. 2011;6(1):17–22. https://doi.org/10.2174/157488611794479946.

    Article  CAS  PubMed  Google Scholar 

  74. Bozok Cetintaş V, Erer OF, Kosova B, Ozdemir I, Topçuoğlu N, Aktoğu S, et al. Determining the relation between N-acetyltransferase-2 acetylator phenotype and antituberculosis drug induced hepatitis by molecular biologic tests. Tuberk Toraks. 2008;56(1):81–6.

    PubMed  Google Scholar 

  75. Ho HT, Wang TH, Hsiong CH, Perng WC, Wang NC, Huang TY, et al. The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity. Pharmacogenet Genomics. 2013;23(4):200–7. https://doi.org/10.1097/FPC.0b013e32835e95e1.

    Article  CAS  PubMed  Google Scholar 

  76. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis. 2000;4(3):256–61.

    CAS  PubMed  Google Scholar 

  77. Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology. 2002;35(4):883–9. https://doi.org/10.1053/jhep.2002.32102.

    Article  CAS  PubMed  Google Scholar 

  78. Shimizu Y, Dobashi K, Mita Y, Endou K, Moriya S, Osano K, et al. DNA microarray genotyping of N-acetyltransferase 2 polymorphism using carbodiimide as the linker for assessment of isoniazid hepatotoxicity. Tuberculosis (Edinb). 2006;86(5):374–81. https://doi.org/10.1016/j.tube.2005.09.002.

    Article  CAS  PubMed  Google Scholar 

  79. Yimer G, Ueda N, Habtewold A, Amogne W, Suda A, Riedel KD, et al. Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients. PLoS One. 2011;6(12):e27810. https://doi.org/10.1371/journal.pone.0027810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. An HR, Wu XQ, Wang ZY, Zhang JX, Liang Y. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol. 2012;39(6):535–43. https://doi.org/10.1111/j.1440-1681.2012.05713.x.

    Article  CAS  PubMed  Google Scholar 

  81. Costa GN, Magno LA, Santana CV, Konstantinovas C, Saito ST, Machado M, et al. Genetic interaction between NAT2, GSTM1, GSTT1, CYP2E1, and environmental factors is associated with adverse reactions to anti-tuberculosis drugs. Mol Diagn Ther. 2012;16(4):241–50. https://doi.org/10.1007/bf03262213.

    Article  CAS  PubMed  Google Scholar 

  82. Gupta VH, Amarapurkar DN, Singh M, Sasi P, Joshi JM, Baijal R, et al. Association of N-acetyltransferase 2 and cytochrome P450 2E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India. J Gastroenterol Hepatol. 2013;28(8):1368–74. https://doi.org/10.1111/jgh.12194.

    Article  CAS  PubMed  Google Scholar 

  83. Santos NP, Callegari-Jacques SM, Ribeiro Dos Santos AK, Silva CA, Vallinoto AC, Fernandes DC, et al. N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients. Int J Tuberc Lung Dis. 2013;17(4):499-504. https://doi.org/10.5588/ijtld.12.0645.

  84. Bose PD, Sarma MP, Medhi S, Das BC, Husain SA, Kar P. Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. J Gastroenterol Hepatol. 2011;26(2):312–8. https://doi.org/10.1111/j.1440-1746.2010.06355.x.

    Article  CAS  PubMed  Google Scholar 

  85. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003;37(4):924–30. https://doi.org/10.1053/jhep.2003.50144.

    Article  CAS  PubMed  Google Scholar 

  86. Ben Mahmoud L, Ghozzi H, Kamoun A, Hakim A, Hachicha H, Hammami S, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathol Biol (Paris). 2012;60(5):324–30. https://doi.org/10.1016/j.patbio.2011.07.001.

    Article  CAS  PubMed  Google Scholar 

  87. Sotsuka T, Sasaki Y, Hirai S, Yamagishi F, Ueno K. Association of isoniazid-metabolizing enzyme genotypes and isoniazid-induced hepatotoxicity in tuberculosis patients. In Vivo. 2011;25(5):803–12.

    CAS  PubMed  Google Scholar 

  88. Du H, Chen X, Fang Y, Yan O, Xu H, Li L, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep. 2013;40(5):3591–6. https://doi.org/10.1007/s11033-012-2433-y.

    Article  CAS  PubMed  Google Scholar 

  89. Yamada S, Tang M, Richardson K, Halaschek-Wiener J, Chan M, Cook VJ, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics. 2009;10(9):1433–45. https://doi.org/10.2217/pgs.09.66.

    Article  CAS  PubMed  Google Scholar 

  90. Lv X, Tang S, Xia Y, Zhang Y, Wu S, Yang Z, et al. NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population. Ann Hepatol. 2012;11(5):700–7.

    Article  CAS  PubMed  Google Scholar 

  91. Leiro-Fernandez V, Valverde D, Vázquez-Gallardo R, Botana-Rial M, Constenla L, Agúndez JA, et al. N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians. Int J Tuberc Lung Dis. 2011;15(10):1403–8. https://doi.org/10.5588/ijtld.10.0648.

    Article  CAS  PubMed  Google Scholar 

  92. Roy B, Ghosh SK, Sutradhar D, Sikdar N, Mazumder S, Barman S. Predisposition of antituberculosis drug induced hepatotoxicity by cytochrome P450 2E1 genotype and haplotype in pediatric patients. J Gastroenterol Hepatol. 2006;21(4):784–6. https://doi.org/10.1111/j.1440-1746.2006.04197.x.

    Article  CAS  PubMed  Google Scholar 

  93. Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. 2006;62(6):423–9. https://doi.org/10.1007/s00228-006-0111-5.

    Article  CAS  PubMed  Google Scholar 

  94. Perwitasari DA, Atthobari J, Wilffert B. Pharmacogenetics of isoniazid-induced hepatotoxicity. Drug Metab Rev. 2015;47(2):222–8. https://doi.org/10.3109/03602532.2014.984070.

    Article  CAS  PubMed  Google Scholar 

  95. Cai Y, Yi J, Zhou C, Shen X. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One. 2012;7(10):e47769. https://doi.org/10.1371/journal.pone.0047769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2007;3(1):1–8. https://doi.org/10.1517/17425255.3.1.1.

    Article  PubMed  Google Scholar 

  97. Roy PD, Majumder M, Roy B. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics. 2008;9(3):311–21. https://doi.org/10.2217/14622416.9.3.311.

    Article  PubMed  Google Scholar 

  98. Singla N, Gupta D, Birbian N, Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis (Edinb). 2014;94(3):293–8. https://doi.org/10.1016/j.tube.2014.02.003.

    Article  CAS  PubMed  Google Scholar 

  99. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049–57. https://doi.org/10.1056/NEJMoa042934.

    Article  CAS  PubMed  Google Scholar 

  100. Haegele KD, Talseth T, Skrdlant HB, Shepherd AM, Huff SL. Determination of hydralazine pyruvic acid hydrazone and its correlation with “apparent” hydralazine. Arzneimittelforschung. 1981;31(2):357–62.

    CAS  PubMed  Google Scholar 

  101. Schulert AR. Physiological disposition of hydralazine (1-hydrazinophthalazine) and a method for its determination in biological fluids. Arch Int Pharmacodyn Ther. 1961;132:1–15.

    CAS  PubMed  Google Scholar 

  102. Talseth T. Studies on hydralazine. III. Bioavailability of hydralazine in man. Eur J Clin Pharmacol. 1976;10(6):395-401. https://doi.org/10.1007/bf00563075.

  103. Timbrell JA, Harland SJ, Facchini V. Polymorphic acetylation of hydralazine. Clin Pharmacol Ther. 1980;28(3):350–5. https://doi.org/10.1038/clpt.1980.173.

    Article  CAS  PubMed  Google Scholar 

  104. Weber WW, Hein DW. N-acetylation pharmacogenetics. Pharmacol Rev. 1985;37(1):25–79.

    CAS  PubMed  Google Scholar 

  105. Schmid K, Küng W, Riess W, Dollery CT, Harland SJ. Metabolism of hydralazine in man. Investigation of features relevant to drug safety, Part I. Arzneimittelforschung. 1981;31(7):1143–11477.

  106. •• Collins KS, Raviele ALJ, Elchynski AL, Woodcock AM, Zhao Y, Cooper-DeHoff RM, et al. Genotype-Guided Hydralazine Therapy. Am J Nephrol. 2020;51(10):764–76. https://doi.org/10.1159/000510433. (This study concluded that with appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safer treatment of resistant hypertension.)

    Article  CAS  PubMed  Google Scholar 

  107. Arce C, Pérez-Plasencia C, González-Fierro A, de la Cruz-Hernández E, Revilla-Vázquez A, Chávez-Blanco A, et al. A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer. PLoS One. 2006;1(1): e98. https://doi.org/10.1371/journal.pone.0000098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Candelaria M, Gallardo-Rincón D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol. 2007;18(9):1529–38. https://doi.org/10.1093/annonc/mdm204.

    Article  CAS  PubMed  Google Scholar 

  109. Arbor Pharmaceuticals LLC, online. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020727s010lbl.pdf. Accessed August 27, 2021.

  110. Novartis online. 1996. https://www.accessdata.fda.gov/drugsatfda_docs/label/1996/008303s068lbl.pdf. Accessed August 27, 2021.

  111. FDA, online. 2021. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed 08/27/2021.

  112. Graves DA, Muir KT, Richards W, Steiger BW, Chang I, Patel B. Hydralazine dose-response curve analysis. J Pharmacokinet Biopharm. 1990;18(4):279–91. https://doi.org/10.1007/bf01062269.

    Article  CAS  PubMed  Google Scholar 

  113. Jounela AJ, Pasanen M, Mattila MJ. Acetylator phenotype and the antihypertensive response to hydralazine. Acta Med Scand. 1975;197(4):303–6. https://doi.org/10.1111/j.0954-6820.1975.tb04922.x.

    Article  CAS  PubMed  Google Scholar 

  114. Kalowski S, Hua AS, Whitworth JA, Kincaid-Smith P. Hydrallazine with beta-blocker and diuretic in the treatment of hypertension. A double-blind crossover study. Med J Aust. 1979;2(8):439-40.

  115. Rowell NP, Clark K. The effects of oral hydralazine on blood pressure, cardiac output and peripheral resistance with respect to dose, age and acetylator status. Radiother Oncol. 1990;18(4):293–8. https://doi.org/10.1016/0167-8140(90)90109-a.

    Article  CAS  PubMed  Google Scholar 

  116. Shepherd A, Lin MS, McNay J, Ludden T, Musgrave G. Determinants of response to intravenous hydralazine in hypertension. Clin Pharmacol Ther. 1981;30(6):773–81. https://doi.org/10.1038/clpt.1981.237.

    Article  CAS  PubMed  Google Scholar 

  117. Shepherd AM, McNay JL, Ludden TM, Lin MS, Musgrave GE. Plasma concentration and acetylator phenotype determine response to oral hydralazine. Hypertension. 1981;3(5):580–5. https://doi.org/10.1161/01.hyp.3.5.580.

    Article  CAS  PubMed  Google Scholar 

  118. Hunyor SN. Hydrallazine and beta-blockade in refractory hypertension with characterization of acetylator phenotype. Aust N Z J Med. 1975;5(6):530–6. https://doi.org/10.1111/j.1445-5994.1975.tb03857.x.

    Article  CAS  PubMed  Google Scholar 

  119. Spinasse LB, Santos AR, Suffys PN, Muxfeldt ES, Salles GF. Different phenotypes of the NAT2 gene influences hydralazine antihypertensive response in patients with resistant hypertension. Pharmacogenomics. 2014;15(2):169–78. https://doi.org/10.2217/pgs.13.202.

    Article  CAS  PubMed  Google Scholar 

  120. Sherry ST, Ward M, Sirotkin K. dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res. 1999;9(8):677–9.

    Article  CAS  PubMed  Google Scholar 

  121. Batchelor JR, Welsh KI, Tinoco RM, Dollery CT, Hughes GR, Bernstein R, et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet. 1980;1(8178):1107–9. https://doi.org/10.1016/s0140-6736(80)91554-8.

    Article  CAS  PubMed  Google Scholar 

  122. Cameron HA, Ramsay LE. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br Med J (Clin Res Ed). 1984;289(6442):410–2. https://doi.org/10.1136/bmj.289.6442.410.

    Article  CAS  Google Scholar 

  123. Ihle BU, Whitworth JA, Dowling JP, Kincaid-Smith P. Hydralazine and lupus nephritis. Clin Nephrol. 1984;22(5):230–8.

    CAS  PubMed  Google Scholar 

  124. Hoffmann BFRM, Wit AL. The action of quinidine and procaine amide on single fiber of dog ventricule and specialized conducting system. An Acad Bras Cienc. 1958;29:365.

    Google Scholar 

  125. Hoffman BF, Rosen MR, Wit AL. Electrophysiology and pharmacology of cardiac arrhythmias. VII. Cardiac effects of quinidine and procaine amide. A. Am Heart J. 1975;89(6):804-8. https://doi.org/10.1016/0002-8703(75)90197-0.

  126. Woske H, Belford J, Fastier FN, Brooks CM. The effect of procaine amide on excitability, refractoriness and conduction in the mammalian heart. J Pharmacol Exp Ther. 1953;107(2):134–40.

    CAS  PubMed  Google Scholar 

  127. Giardina EG. Procainamide: clinical pharmacology and efficacy against ventricular arrhythmias. Ann N Y Acad Sci. 1984;432:177–88. https://doi.org/10.1111/j.1749-6632.1984.tb14519.x.

    Article  CAS  PubMed  Google Scholar 

  128. Somani R, Krahn AD, Healey JS, Chauhan VS, Birnie DH, Champagne J, et al. Procainamide infusion in the evaluation of unexplained cardiac arrest: from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER). Heart Rhythm. 2014;11(6):1047–54. https://doi.org/10.1016/j.hrthm.2014.03.022.

    Article  PubMed  Google Scholar 

  129. Giardina EG, Dreyfuss J, Bigger JT Jr, Shaw JM, Schreiber EC. Metabolism of procainamide in normal and cardiac subjects. Clin Pharmacol Ther. 1976;19(3):339–51. https://doi.org/10.1002/cpt1976193339.

    Article  CAS  PubMed  Google Scholar 

  130. Graffner C, Johnsson G, Sjögren J. Pharmacokinetics of procainamide intravenously and orally as conventional and slow-release tablets. Clin Pharmacol Ther. 1975;17(4):414–23. https://doi.org/10.1002/cpt1975174414.

    Article  CAS  PubMed  Google Scholar 

  131. Taber DF, Jernigan JD, Watson JT, Carr K, Woosley RL. N-Desethyacecainide is a metabolite of procainamide in man; convenient method for the preparation of an N-dealkylated drug metabolite. Drug Metab Dispos. 1979;7(5):346.

    CAS  PubMed  Google Scholar 

  132. Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, et al. Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide. Am J Cardiol. 1980;46(3):463–8. https://doi.org/10.1016/0002-9149(80)90016-8.

    Article  CAS  PubMed  Google Scholar 

  133. Giardina EG, Stein RM, Bigger JT. The relationship between the metabolism of procainamide and sulfamethazine. Circulation. 1977;55(2):388–94. https://doi.org/10.1161/01.cir.55.2.388.

    Article  CAS  Google Scholar 

  134. Woosley RL, Drayer DE, Reidenberg MM, Nies AS, Carr K, Oates JA. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med. 1978;298(21):1157–9. https://doi.org/10.1056/nejm197805252982101.

    Article  CAS  PubMed  Google Scholar 

  135. Henningsen NC, Cederberg A, Hanson A, Johansson BW. Effects of long-term treatment with procaine amide. A prospective study with special regard to ANF and SLE in fast and slow acetylators. Acta Med Scand. 1975;198(6):475–482.

  136. Kosowsky BD, Taylor J, Lown B, Ritchie RF. Long-term use of procaine amide following acute myocardial infarction. Circulation. 1973;47(6):1204–10. https://doi.org/10.1161/01.cir.47.6.1204.

    Article  CAS  PubMed  Google Scholar 

  137. Freeman RW, Woosley RL, Oates JA, Harbison RD. Evidence for the biotransformation of procainamide to a reactive metabolite. Toxicol Appl Pharmacol. 1979;50(1):9–16. https://doi.org/10.1016/0041-008x(79)90486-1.

    Article  CAS  PubMed  Google Scholar 

  138. Uetrecht JP, Woosley RL, Freeman RW, Sweetman BJ, Oates JA. Metabolism of procainamide in the perfused rat liver. Drug Metab Dispos. 1981;9(3):183–7.

    CAS  PubMed  Google Scholar 

  139. Lessard E, Fortin A, Bélanger PM, Beaune P, Hamelin BA, Turgeon J. Role of CYP2D6 in the N-hydroxylation of procainamide. Pharmacogenetics. 1997;7(5):381–90. https://doi.org/10.1097/00008571-199710000-00007.

    Article  CAS  PubMed  Google Scholar 

  140. Lessard E, 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(6):683–96. https://doi.org/10.1097/01213011-199912000-00003.

    Article  CAS  PubMed  Google Scholar 

  141. Giardina EG, Fenster PE, Bigger JT Jr, Mayersohn M, Perrier D, Marcus FI. Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation. Am J Cardiol. 1980;46(5):855–62. https://doi.org/10.1016/0002-9149(80)90440-3.

    Article  CAS  PubMed  Google Scholar 

  142. Uetrecht JP, Zahid N. N-Chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications. Chem Res Toxicol. 1991;4(2):218–22. https://doi.org/10.1021/tx00020a015.

    Article  CAS  PubMed  Google Scholar 

  143. Warburg O, Christian W. Uber ein neues Oxydationsferment und sein Absorptionsspektrum. Biochem z. 1932;254:438.

    CAS  Google Scholar 

  144. Luzzatto L, Battistuzzi G. Glucose-6-phosphate dehydrogenase. Adv Hum Genet. 1985;14(217–329):86–8. https://doi.org/10.1007/978-1-4615-9400-0_4.

    Article  Google Scholar 

  145. Pai GS, Sprenkle JA, Do TT, Mareni CE, Migeon BR. Localization of loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase and biochemical evidence of nonrandom X chromosome expression from studies of a human X-autosome translocation. Proc Natl Acad Sci U S A. 1980;77(5):2810–3. https://doi.org/10.1073/pnas.77.5.2810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hockwald RS, Arnold J, Clayman CB, Alving AS. Toxicity of primaquine in Negroes. J Am Med Assoc. 1952;149(17):1568–70. https://doi.org/10.1001/jama.1952.72930340027010c.

    Article  CAS  PubMed  Google Scholar 

  147. Clayman CB, Arnold J, Hockwald RS, Yount EH Jr, Edgcomb JH, Alving AS. Toxicity of primaquine in Caucasians. J Am Med Assoc. 1952;149(17):1563–8. https://doi.org/10.1001/jama.1952.72930340022010b.

    Article  CAS  PubMed  Google Scholar 

  148. Alving AS, Carson PE, Flanagan CL, Ickes CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956;124(3220):484–5. https://doi.org/10.1126/science.124.3220.484-a.

    Article  CAS  PubMed  Google Scholar 

  149. Beutler E, Vulliamy TJ. Hematologically important mutations: glucose-6-phosphate dehydrogenase. Blood Cells Mol Dis. 2002;28(2):93–103. https://doi.org/10.1006/bcmd.2002.0490.

    Article  PubMed  Google Scholar 

  150. Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009;42(3):267–78. https://doi.org/10.1016/j.bcmd.2008.12.005.

    Article  CAS  PubMed  Google Scholar 

  151. Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev. 2007;21(5):267–83. https://doi.org/10.1016/j.blre.2007.05.002.

    Article  CAS  PubMed  Google Scholar 

  152. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64–74. https://doi.org/10.1016/s0140-6736(08)60073-2.

    Article  CAS  PubMed  Google Scholar 

  153. De Vita G, Alcalay M, Sampietro M, Cappelini MD, Fiorelli G, Toniolo D. Two point mutations are responsible for G6PD polymorphism in Sardinia. Am J Hum Genet. 1989;44(2):233–40.

    PubMed  PubMed Central  Google Scholar 

  154. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ. 1989;67(6):601–611.

  155. Vulliamy T, Beutler E, Luzzatto L. Variants of glucose-6-phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene. Hum Mutat. 1993;2(3):159–67. https://doi.org/10.1002/humu.1380020302.

    Article  CAS  PubMed  Google Scholar 

  156. Yoshida A, Beutler E, Motulsky AG. Human glucose-6-phosphate dehydrogenase variants. Bull World Health Organ. 1971;45(2):243–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Iwai K, Hirono A, Matsuoka H, Kawamoto F, Horie T, Lin K, et al. Distribution of glucose-6-phosphate dehydrogenase mutations in Southeast Asia. Hum Genet. 2001;108(6):445–9. https://doi.org/10.1007/s004390100527.

    Article  CAS  PubMed  Google Scholar 

  158. Vulliamy TJ, D’Urso M, Battistuzzi G, Estrada M, Foulkes NS, Martini G, et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988;85(14):5171–5. https://doi.org/10.1073/pnas.85.14.5171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Manco L, Pereira J, Relvas L, Rebelo U, Crisóstomo AI, Bento C, et al. Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman. Blood Cells Mol Dis. 2011;46(4):288–93. https://doi.org/10.1016/j.bcmd.2011.02.001.

    Article  CAS  PubMed  Google Scholar 

  160. Beutler E. G6PD deficiency. Blood. 1994;84(11):3613–36.

    Article  CAS  PubMed  Google Scholar 

  161. Beutler E, Yeh M, Fairbanks VF. The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A. 1962;48(1):9–16. https://doi.org/10.1073/pnas.48.1.9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Leslie T, Briceño M, Mayan I, Mohammed N, Klinkenberg E, Sibley CH, et al. The impact of phenotypic and genotypic G6PD deficiency on risk of plasmodium vivax infection: a case-control study amongst Afghan refugees in Pakistan. PLoS Med. 2010;7(5):e1000283. https://doi.org/10.1371/journal.pmed.1000283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Luzzatto L. Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica. 2006;91(10):1303–6.

    CAS  PubMed  Google Scholar 

  164. FDA, online. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008316s022lbl.pdf. Accessed August 31, 2021.

  165. •• Recht J, Ashley EA, White NJ. Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries. PLoS Negl Trop Dis. 2018;12(4):e0006230. https://doi.org/10.1371/journal.pntd.0006230. (This study reviews available information on the prevalence and severity of G6PD variants together with countries' policies for the use of primaquine and G6PD deficiency testing.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Beutler E, Dern RJ, Alving AS. The hemolytic effect of primaquine. IV. The relationship of cell age to hemolysis. J Lab Clin Med. 1954;44(3):439–442.

  167. WHO. Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Updated WHO Policy Recommendation (October 2012). Global Malaria Programme online https://www.who.int/malaria/pq_updated_policy_recommendation_en_102012.pdf2012. p. 1. Accessed Aug 2021.

  168. Chu CS, Bancone G, Moore KA, Win HH, Thitipanawan N, Po C, et al. Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens. PLoS Med. 2017;14(2): e1002224. https://doi.org/10.1371/journal.pmed.1002224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ashley EA, Recht J, White NJ. Primaquine: the risks and the benefits. Malar J. 2014;13:418. https://doi.org/10.1186/1475-2875-13-418.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41. https://doi.org/10.1016/j.pharmthera.2012.12.007.

    Article  CAS  PubMed  Google Scholar 

  171. Pybus BS, Marcsisin SR, Jin X, Deye G, Sousa JC, Li Q, et al. The metabolism of primaquine to its active metabolite is dependent on CYP 2D6. Malar J. 2013;12:212. https://doi.org/10.1186/1475-2875-12-212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Cortes J, Moore JO, Maziarz RT, Wetzler M, Craig M, Matous J, et al. Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone–results of a multicenter phase III study. J Clin Oncol. 2010;28(27):4207–13. https://doi.org/10.1200/jco.2009.26.8896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26(16):2767–78. https://doi.org/10.1200/jco.2007.15.0177.

    Article  CAS  PubMed  Google Scholar 

  174. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127(1):3–11. https://doi.org/10.1111/j.1365-2141.2004.05094.x.

    Article  PubMed  Google Scholar 

  175. Darmon M, Guichard I, Vincent F, Schlemmer B, Azoulay E. Prognostic significance of acute renal injury in acute tumor lysis syndrome. Leuk Lymphoma. 2010;51(2):221–7. https://doi.org/10.3109/10428190903456959.

    Article  PubMed  Google Scholar 

  176. Relling MV, McDonagh EM, Chang T, Caudle KE, McLeod HL, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther. 2014;96(2):169–74. https://doi.org/10.1038/clpt.2014.97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Nguyen AP, Ness GL. Hemolytic anemia following rasburicase administration: a review of published reports. J Pediatr Pharmacol Ther. 2014;19(4):310–6. https://doi.org/10.5863/1551-6776-19.4.310.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599–606.

    PubMed  Google Scholar 

  179. Bauters T, Mondelaers V, Robays H, De Wilde H, Benoit Y, De Moerloose B. Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia. Int J Clin Pharm. 2011;33(1):58–60. https://doi.org/10.1007/s11096-011-9484-3.

    Article  CAS  PubMed  Google Scholar 

  180. Browning LA, Kruse JA. Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother. 2005;39(11):1932–5. https://doi.org/10.1345/aph.1G272.

    Article  PubMed  Google Scholar 

  181. Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov J, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010;33(9):713–26. https://doi.org/10.2165/11536520-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  182. Chan TK, Todd D, Tso SC. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency. Br Med J. 1976;2(6046):1227–9. https://doi.org/10.1136/bmj.2.6046.1227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Lavelle KJ, Atkinson KF, Kleit SA. Hyperlactatemia and hemolysis in G6PD deficiency after nitrofurantoin ingestion. Am J Med Sci. 1976;272(2):201–4. https://doi.org/10.1097/00000441-197609000-00010.

    Article  CAS  PubMed  Google Scholar 

  184. West M, Zimmerman HJ. Hemolytic anemia in patient receiving nitrofurantoin (furadantin). J Am Med Assoc. 1956;162(7):637–9. https://doi.org/10.1001/jama.1956.72970240001008.

    Article  CAS  PubMed  Google Scholar 

  185. Powell RDAA, Degowin RL. Nitrofurantoin-induced hemolysis. J Lab Clin Med. 1963;62(6):1002–3.

    Google Scholar 

  186. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med. 1991;324(3):169–74. https://doi.org/10.1056/nejm199101173240306.

    Article  CAS  PubMed  Google Scholar 

  187. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333(24):1600–7. https://doi.org/10.1056/nejm199512143332404.

    Article  CAS  PubMed  Google Scholar 

  188. McKenna JK, Leiferman KM. Dermatologic drug reactions. Immunol Allergy Clin North Am. 2004;24(3):399-423, vi. https://doi.org/10.1016/j.iac.2004.03.007.

  189. Klein J. Seeds of time: fifty years ago Peter A. Gorer discovered the H-2 complex. Immunogenetics. 1986;24(6):331-8. https://doi.org/10.1007/bf00377947.

  190. Thorsby E. A short history of HLA. Tissue Antigens. 2009;74(2):101–16. https://doi.org/10.1111/j.1399-0039.2009.01291.x.

    Article  CAS  PubMed  Google Scholar 

  191. FDA, online. 1998. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20-977_ZIAGEN_APPROV.PDF. Accessed October 08, 2021.

  192. online. 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/ziagen. Accessed October 08, 2021.

  193. Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. 2001;23(10):1603–14. https://doi.org/10.1016/s0149-2918(01)80132-6.

    Article  CAS  PubMed  Google Scholar 

  194. Hernandez JE CA, Edwards M, et al. . Program and abstracts of the Clinical risk factors for hypersensitivity reactions to abacavir: retrospective analysis of over 8000 subjects receiving abacavir in 34 clinical trials. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL2003.

  195. Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A. 2004;101(12):4180–5. https://doi.org/10.1073/pnas.0307067101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Peyrieère H, Nicolas J, Siffert M, Demoly P, Hillaire-Buys D, Reynes J. Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother. 2001;35(10):1291–2. https://doi.org/10.1345/aph.1A022.

    Article  PubMed  Google Scholar 

  197. Easterbrook PJ, Waters A, Murad S, Ives N, Taylor C, King D, et al. Epidemiological risk factors for hypersensitivity reactions to abacavir. HIV Med. 2003;4(4):321–4. https://doi.org/10.1046/j.1468-1293.2003.00166.x.

    Article  CAS  PubMed  Google Scholar 

  198. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359(9312):1121–2. https://doi.org/10.1016/s0140-6736(02)08158-8.

    Article  CAS  PubMed  Google Scholar 

  199. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727–32. https://doi.org/10.1016/s0140-6736(02)07873-x.

    Article  CAS  PubMed  Google Scholar 

  200. Sun HY, Hung CC, Lin PH, Chang SF, Yang CY, Chang SY, et al. Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan. J Antimicrob Chemother. 2007;60(3):599–604. https://doi.org/10.1093/jac/dkm243.

    Article  CAS  PubMed  Google Scholar 

  201. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111–8. https://doi.org/10.1086/529382.

    Article  CAS  PubMed  Google Scholar 

  202. Hughes AR, Mosteller M, Bansal AT, Davies K, Haneline SA, Lai EH, et al. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics. 2004;5(2):203–11. https://doi.org/10.1517/phgs.5.2.203.27481.

    Article  CAS  PubMed  Google Scholar 

  203. Norcross MA, Luo S, Lu L, Boyne MT, Gomarteli M, Rennels AD, et al. Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity. Aids. 2012;26(11):F21-9. https://doi.org/10.1097/QAD.0b013e328355fe8f.

    Article  CAS  PubMed  Google Scholar 

  204. Ostrov DA, Grant BJ, Pompeu YA, Sidney J, Harndahl M, Southwood S, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S A. 2012;109(25):9959–64. https://doi.org/10.1073/pnas.1207934109.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature. 2012;486(7404):554–8. https://doi.org/10.1038/nature11147.

    Article  CAS  PubMed  Google Scholar 

  206. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79. https://doi.org/10.1056/NEJMoa0706135.

    Article  PubMed  Google Scholar 

  207. Orkin C, Wang J, Bergin C, Molina JM, Lazzarin A, Cavassini M, et al. An epidemiologic study to determine the prevalence of the HLA-B*5701 allele among HIV-positive patients in Europe. Pharmacogenet Genomics. 2010;20(5):307–14. https://doi.org/10.1097/FPC.0b013e3283390666.

    Article  CAS  PubMed  Google Scholar 

  208. Arrizabalaga J, Rodriguez-Alcántara F, Castañer JL, Ocampo A, Podzamczer D, Pulido F, et al. Prevalence of HLA-B*5701 in HIV-infected patients in Spain (results of the EPI Study). HIV Clin Trials. 2009;10(1):48–51. https://doi.org/10.1310/hct1001-048.

    Article  CAS  PubMed  Google Scholar 

  209. Orkin C, Sadiq ST, Rice L, Jackson F. Prospective epidemiological study of the prevalence of human leukocyte antigen (HLA)-B*5701 in HIV-1-infected UK subjects. HIV Med. 2010;11(3):187–92. https://doi.org/10.1111/j.1468-1293.2009.00762.x.

    Article  CAS  PubMed  Google Scholar 

  210. Martin MA, Klein TE, Dong BJ, Pirmohamed M, Haas DW, Kroetz DL. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther. 2012;91(4):734–8. https://doi.org/10.1038/clpt.2011.355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Cao K, Hollenbach J, Shi X, Shi W, Chopek M, Fernández-Viña MA. Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Hum Immunol. 2001;62(9):1009–30. https://doi.org/10.1016/s0198-8859(01)00298-1.

    Article  CAS  PubMed  Google Scholar 

  212. Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis. 2006;43(1):99–102. https://doi.org/10.1086/504874.

    Article  CAS  PubMed  Google Scholar 

  213. Reeves I, Churchill D, Fisher M. Screening for HLA-B*5701 reduces the frequency of abacavir hypersensitivity reactions. Antiviral Therapy. 2006;Supplement L11-L11.

  214. Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Sutherland-Phillips DH, et al. Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-boosted atazanavir in HIV-infected patients. HIV Clin Trials. 2010;11(2):69–79. https://doi.org/10.1310/hct1102-69.

    Article  CAS  PubMed  Google Scholar 

  215. •• Stainsby CM, Perger TM, Vannappagari V, Mounzer KC, Hsu RK, Henegar CE, et al. Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk-Mitigation Measure. Pharmacotherapy. 2019;39(1):40–54. https://doi.org/10.1002/phar.2196. (This study uses data from the OPERA study and suggested that patients should be confirmed negative for HLA-B*5701 before being started on abacavir.)

    Article  CAS  PubMed  Google Scholar 

  216. McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134–43. https://doi.org/10.1056/NEJMoa1013297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005;209(2):123–9. https://doi.org/10.1016/j.tox.2004.12.022.

    Article  CAS  PubMed  Google Scholar 

  218. Ardern-Jones MR, Friedmann PS. Skin manifestations of drug allergy. Br J Clin Pharmacol. 2011;71(5):672–83. https://doi.org/10.1111/j.1365-2125.2010.03703.x.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Pirmohamed M, Friedmann PS, Molokhia M, Loke YK, Smith C, Phillips E, et al. Phenotype standardization for immune-mediated drug-induced skin injury. Clin Pharmacol Ther. 2011;89(6):896–901. https://doi.org/10.1038/clpt.2011.79.

    Article  CAS  PubMed  Google Scholar 

  220. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64(7):1134–8. https://doi.org/10.1212/01.Wnl.0000156354.20227.F0.

    Article  CAS  PubMed  Google Scholar 

  221. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803–813; quiz 14-5. https://doi.org/10.1586/eci.11.66.

  222. Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet Genomics. 2014;24(2):94–112. https://doi.org/10.1097/fpc.0000000000000021.

    Article  CAS  PubMed  Google Scholar 

  223. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486. https://doi.org/10.1038/428486a.

    Article  CAS  PubMed  Google Scholar 

  224. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025–32. https://doi.org/10.1001/jamadermatol.2013.4114.

    Article  CAS  PubMed  Google Scholar 

  225. Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ, Patel DB, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol. 2009;75(6):579–82. https://doi.org/10.4103/0378-6323.57718.

    Article  PubMed  Google Scholar 

  226. Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008;49(12):2087–91. https://doi.org/10.1111/j.1528-1167.2008.01719.x.

    Article  PubMed  Google Scholar 

  227. Kim SH, Lee KW, Song WJ, Kim SH, Jee YK, Lee SM, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res. 2011;97(1–2):190–7. https://doi.org/10.1016/j.eplepsyres.2011.08.010.

    Article  CAS  PubMed  Google Scholar 

  228. Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, et al. A marker for Stevens-Johnson syndrome …: ethnicity matters. Pharmacogenomics J. 2006;6(4):265–8. https://doi.org/10.1038/sj.tpj.6500356.

    Article  CAS  PubMed  Google Scholar 

  229. Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics. 2006;7(6):813–8. https://doi.org/10.2217/14622416.7.6.813.

    Article  CAS  PubMed  Google Scholar 

  230. Nucleic Acid Research, online. 2020. http://www.allelefrequencies.net/. Accessed September 09,10,14, 2021.

  231. FDA, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01755.html. Accessed December 2007.

  232. Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet. 2011;20(5):1034–41. https://doi.org/10.1093/hmg/ddq537.

    Article  CAS  PubMed  Google Scholar 

  233. Ikeda H, Takahashi Y, Yamazaki E, Fujiwara T, Kaniwa N, Saito Y, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia. 2010;51(2):297–300. https://doi.org/10.1111/j.1528-1167.2009.02269.x.

    Article  PubMed  Google Scholar 

  234. Amstutz U, Ross CJ, Castro-Pastrana LI, Rieder MJ, Shear NH, Hayden MR, et al. HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin Pharmacol Ther. 2013;94(1):142–9. https://doi.org/10.1038/clpt.2013.55.

    Article  CAS  PubMed  Google Scholar 

  235. Genin E, Chen DP, Hung SI, Sekula P, Schumacher M, Chang PY, et al. HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis. Pharmacogenomics J. 2014;14(3):281–8. https://doi.org/10.1038/tpj.2013.40.

    Article  CAS  PubMed  Google Scholar 

  236. Wang Q, Sun S, Xie M, Zhao K, Li X, Zhao Z. Association between the HLA-B alleles and carbamazepine-induced SJS/TEN: A meta-analysis. Epilepsy Res. 2017;135:19–28. https://doi.org/10.1016/j.eplepsyres.2017.05.015.

    Article  CAS  PubMed  Google Scholar 

  237. Mockenhaupt M, Wang CW, Hung SI, Sekula P, Schmidt AH, Pan RY, et al. HLA-B*57:01 confers genetic susceptibility to carbamazepine-induced SJS/TEN in Europeans. Allergy. 2019;74(11):2227–30. https://doi.org/10.1111/all.13821.

    Article  PubMed  Google Scholar 

  238. Reiter S, Simmonds HA, Zöllner N, Braun SL, Knedel M. Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol. Clin Chim Acta. 1990;187(3):221–34. https://doi.org/10.1016/0009-8981(90)90107-4.

    Article  CAS  PubMed  Google Scholar 

  239. Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58(1):25–32. https://doi.org/10.1016/j.jaad.2007.08.036.

    Article  PubMed  Google Scholar 

  240. Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071–1080. https://doi.org/10.1111/bjd.12501.

  241. • Bluestein S, Yu R, Stone C, Phillips E. A review of drug reaction with eosinophilia and systemic symptoms in the FDA adverse event reporting system (FAERS). J Allergy Clin Immunol. 2021;147(2). AB1210.016/j.jaci.2020.12.085 (This study reports that allopurinol, vancomycin, and carbamazepine account for one-third of reported cases and 40% of deaths associated with drug reactions with eosinophilia and systemic symptoms.)

  242. Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res (Hoboken). 2013;65(4):578–84. https://doi.org/10.1002/acr.21817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. • Frey N, Bodmer M, Bircher A, Jick SS, Meier CR, Spoendlin J. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Commonly Prescribed Drugs in Outpatient Care Other than Anti-Epileptic Drugs and Antibiotics: A Population-Based Case-Control Study. Drug Saf. 2019;42(1):55–66. https://doi.org/10.1007/s40264-018-0711-x. (This observational study demonstrated likely causal associations between Stevens-Johnson syndrome/toxic epidermal necrolysis and use of allopurinol, cyclooxygenase-2 inhibitors, and 5-aminosalicylates.)

    Article  PubMed  Google Scholar 

  244. Melsom RD. Familial hypersensitivity to allopurinol with subsequent desensitization. Rheumatology (Oxford). 1999;38(12):1301. https://doi.org/10.1093/rheumatology/38.12.1301.

    Article  CAS  PubMed  Google Scholar 

  245. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102(11):4134–9. https://doi.org/10.1073/pnas.0409500102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. 2009;19(9):704–9. https://doi.org/10.1097/FPC.0b013e328330a3b8.

    Article  CAS  PubMed  Google Scholar 

  247. Kang HR, Jee YK, Kim YS, Lee CH, Jung JW, Kim SH, et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics. 2011;21(5):303–7. https://doi.org/10.1097/FPC.0b013e32834282b8.

    Article  CAS  PubMed  Google Scholar 

  248. Chiu ML, Hu M, Ng MH, Yeung CK, Chan JC, Chang MM, et al. Association between HLA-B*58:01 allele and severe cutaneous adverse reactions with allopurinol in Han Chinese in Hong Kong. Br J Dermatol. 2012;167(1):44–9. https://doi.org/10.1111/j.1365-2133.2012.10894.x.

    Article  CAS  PubMed  Google Scholar 

  249. Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Chaiyakunapruk N. Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med Genet. 2011;12:118. https://doi.org/10.1186/1471-2350-12-118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics. 2008;9(11):1617–22. https://doi.org/10.2217/14622416.9.11.1617.

    Article  CAS  PubMed  Google Scholar 

  251. Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics. 2008;18(2):99–107. https://doi.org/10.1097/FPC.0b013e3282f3ef9c.

    Article  CAS  PubMed  Google Scholar 

  252. Tohkin M, Kaniwa N, Saito Y, Sugiyama E, Kurose K, Nishikawa J, et al. A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J. 2013;13(1):60–9. https://doi.org/10.1038/tpj.2011.41.

    Article  CAS  PubMed  Google Scholar 

  253. Gonçalo M, Coutinho I, Teixeira V, Gameiro AR, Brites MM, Nunes R, et al. HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis in a Portuguese population. Br J Dermatol. 2013;169(3):660–5. https://doi.org/10.1111/bjd.12389.

    Article  CAS  PubMed  Google Scholar 

  254. Keller SF, Lu N, Blumenthal KG, Rai SK, Yokose C, Choi JWJ, et al. Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study. Ann Rheum Dis. 2018;77(8):1187–93. https://doi.org/10.1136/annrheumdis-2017-212905.

    Article  CAS  PubMed  Google Scholar 

  255. Ko TM, Tsai CY, Chen SY, Chen KS, Yu KH, Chu CS, et al. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. Bmj. 2015;351: h4848. https://doi.org/10.1136/bmj.h4848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Yu KH, Yu CY, Fang YF. Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis. Int J Rheum Dis. 2017;20(9):1057–71. https://doi.org/10.1111/1756-185x.13143.

    Article  CAS  PubMed  Google Scholar 

  257. Chong HY, Lim YH, Prawjaeng J, Tassaneeyakul W, Mohamed Z, Chaiyakunapruk N. Cost-effectiveness analysis of HLA-B*58: 01 genetic testing before initiation of allopurinol therapy to prevent allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in a Malaysian population. Pharmacogenet Genomics. 2018;28(2):56–67. https://doi.org/10.1097/fpc.0000000000000319.

    Article  CAS  PubMed  Google Scholar 

  258. Jutkowitz E, Dubreuil M, Lu N, Kuntz KM, Choi HK. The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States. Semin Arthritis Rheum. 2017;46(5):594–600. https://doi.org/10.1016/j.semarthrit.2016.10.009.

    Article  PubMed  Google Scholar 

  259. FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744–60. https://doi.org/10.1002/acr.24180.

    Article  PubMed  Google Scholar 

  260. •• Park HW, Kim DK, Kim SH, Kim S, Chae DW, Yang MS, et al. Efficacy of the HLA-B(∗)58:01 Screening Test in Preventing Allopurinol-Induced Severe Cutaneous Adverse Reactions in Patients with Chronic Renal Insufficiency-A Prospective Study. J Allergy Clin Immunol Pract. 2019;7(4):1271–6. https://doi.org/10.1016/j.jaip.2018.12.012. (This study demonstrated the clinical usefulness of the HLA-B∗∗58:01 screening test before allopurinol administration to prevent allopurinol-induced serious cutaneous adverse reactions in patients with chronic renal insufficiency.)

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Dana Filippoli for her comprehensive review and comments pertaining to this manuscript.

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  1. Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, 13485 Veterans Way, Suite 410, Orlando, FL, 32827, USA

    Veronique Michaud, Pamela Dow & Jacques Turgeon

  2. Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, H3C 3J7, Canada

    Veronique Michaud, Lucy I. Darakjian & Jacques Turgeon

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Veronique Michaud and Jacques Turgeon contributed to the manuscript conception and design. Literature review and analysis were performed by all authors. The first draft of the manuscript was written and critically revised by all authors. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jacques Turgeon.

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The authors declare no competing interests. All authors are employees and shareholders of Tabula Rasa HealthCare.

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Michaud, V., Darakjian, L.I., Dow, P. et al. Role of Pharmacogenomics in Reducing the Risk of Drug-Related Iatrogenesis. Curr Pharmacol Rep 8, 79–98 (2022). https://doi.org/10.1007/s40495-021-00280-7

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