PHARMACOGENETIC ASPECTS OF THE EFFICACY AND SAFETY OF LEUKOTRIENE MODIFIERS IN BRONCHIAL ASTHMA THERAPY

DOI: https://doi.org/10.29296/24999490-2018-06-04

A.K. Zastrozhina(1), D.A. Sychev(2) 1-Children's City Polyclinic No.42, Golubinskaya street, 23/2, Moscow, 117463, Russian Federation; 2-Russian Medical Academy of Postgraduate Education, Barrikadnaya street, 2/1, Moscow, 125993, Russian Federation E-mail: [email protected]

The efficacy of bronchial asthma therapy is one of the most urgent problems in allergology and pulmonology. The efficacy of leukotrienes modifiers in bronchial asthma therapy is not achieved in 35–78% cases. In addition, there are data on unwanted drug reactions associated with leukotriene modifiers. Currently, there is an active search for possible candidate genes that can affect the action of leukotriene modifiers. The purpose of this review was to summarize available information about pharmacogenetic characteristics of leukotriene modifiers and to suspect the interindividual variability mechanisms of their efficacy and safety in bronchial asthma therapy.
Keywords: 
pharmacogenetics, leukotriene modifiers, bronchial asthma
Список литературы: 
  1. Global Strategy For Asthma Management and Prevention. 2018.
  2. Szefler S.J., Phillips B.R., Martinez F.D. Chinchilli V.M., Lemanske R.F., Strunk R.C., Zeiger R.S., Larsen G., Spahn J.D., Bacharier L.B., Bloomberg G.R., Guilbert T.W., Heldt G., Morgan W.J., Moss M.H., Sorkness C.A., Taussig L.M. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J. Allergy Clin. Immunol. 2005; 115: 233–42.
  3. Malmstrom K., Rodriguez-Gomez G., Guerra J., Villaran C., Piñeiro A., Wei L.X., Seidenberg B.C., Reiss T.F. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, con- trolled trial. Montelukast/Beclometha- sone Study Group. Ann Intern Med. 1999; 130: 487–95.
  4. Drazen J.M., Silverman E.K., Lee T.H. Heterogeneity of therapeutic responses in asthma. Br. Med. Bull. 2000; 56: 1054–70.
  5. Chung K.F., Godard P., Adelroth E., Ayres J., Barnes N., Barnes P., Bel E., Burney P., Chanez P., Connett G., Corrigan C., Blic J., Fabbri, L., Holgate S.T., Ind P., Joos G., Kerstjens H., Leuenberger P., Lofdahl C.G., McKenzie S., Magnussen H., Postma D., Saetta M., Salmeron S., Sterk P. Difficult therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society. Eur Respir J. 1999; 13: 1198–208.
  6. Kukes V.G., Starodubceva A.K. Klinicheskaya farmakologiya i farmakoterapiya: uchebnik. Pod red. V.G. Kukesa, A.K. Starodubceva. 3-e izd., dop. i pererab. M.: GE`OTAR-MEDIA, 2012; 832. [Kukes V.G., Starodubceva A.K. Clinical pharmacology and pharmacotherapy: a textbook. Ed. V.G. Kukes, A.K. Starodubtseva. 3rd ed. M.: GE`OTAR-MEDIA, 2012; 832 (in Russian)]
  7. Israel E., Chervinsky P.S., Friedman B., Van Bavel J., Skalky C.S., Ghannam A.F., Bird S.R., Edelman J.M. Effects of montelukast and beclomethasone on airway function and asthma control. J. Allergy Clin. Immunol. 2002; 110 (6): 847–54.
  8. Reinus J.F., Persky S., Burkiewicz J.S., Quan D., Bass N.M., Davern T.J. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med. 2000; 133: 964–8.
  9. Wechsler M.E., Garpestad E., Flier S.R., Kocher O., Weiland D.A., Polito A.J., Klinek M.M., Bigby T.D., Wong G.A., Helmers R.A., Drazen J.M. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA. 1998; 279: 455–7.
  10. Wechsler M.E., Pauwels R., Drazen J.M. Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf. 1999; 21: 241–51.
  11. Jarvis B., Markham A. Montelukast: a review of its therapeutic potential in persistent asthma. Drugs. 2000; 59: 891–928.
  12. Nasonov E.L. Specificheskie ingibitory ciklooksigenazy (COG)-2, reshennye i nereshennye problemy. Klin. farm. ter. 2000; 9 (1): 57–64. [Nasonov E.L. Specific inhibitors of cyclooxygenase-2, solved and unsolved problems. Clin. farm. ter. 2000; 9 (1): 57–64 (in Russian)]
  13. Rang H.P. Pharmacology. – 5th. Edinburg: Churchill Livingstone. 2003; 232–5.
  14. Severin E.S. Biohimiya: Uchebnik dlya VUZov. Pod red. E.S. Severina. M.: GE`OTAR-Media, 2003; 779. [Severin E.S. Biochemistry: Textbook for High Schools. Ed. E.S. Severin. M.: GE`OTAR-Media, 2003; 779 (in Russian)]
  15. Duroudier N.P., Tulah A.S., Sayers I. Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy. 2009; 64 (6): 823–39.
  16. Drazen J.M., Yandava C.N., Dubé L., Szczerback N., Hip-pensteel R., Pillari A., Israel E., Schork N., Silverman E.S., Katz D.A., Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet. 1999; 22 (2): 168–70.
  17. Telleria J.J., Blanco-Quiros A., Varillas D., Armentia A., Fernandez-Carvajal I., Jesus Alonso M., Diez I. ALOX5 promoter genotype and response to montelukast in moderate persistent asthma. Respir Med. 2008; 102 (6): 857–61.
  18. Klotsman M., York T.P., Pillai S.G. Vargas-Irwin C., Sharma S.S., van den Oord E.J., Anderson W.H. Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics. 2007; 17 (3): 189–96.
  19. Fowler S.J., Hall I.P., Wilson A.M., Wheatley A.P., Lipworth B.J. 5-Lipoxygenase polymorphism and in-vivo response to leukotriene receptor antagonists. Eur. J. Clin. Pharmacol. 2002; 58 (3): 187–90.
  20. Lima J.J., Zhang S., Grant A., Shao L., Tantisira K.G., Allayee H., Wang J., Sylvester J., Holbrook J., Wise R., Weiss S.T., Barnes K. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am. J. Respir Crit. Care Med. 2006; 173 (4): 379–85.
  21. Tantisira K.G., Lima J., Sylvia J., Klanderman B., Weiss S.T. 5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci. Pharmacogenet Genomics. 2009; 19 (3): 244–7.
  22. Mougey E.B., Chen C., Tantisira K.G., Blake K.V., Peters S.P., Wise R.A., Weiss S.T., Lima J.J. Pharmacogenetics of asthma controller treatment. Pharmacogenomics J. 2013; 13 (3): 242–50.
  23. Kotani H., Kishi R., Mouri A., Sashio T., Shindo J., Shiraki A., Hiramatsu T., Iwata S., Taniguchi H., Nishiyama O., Iwata M., Suzuki R., Gonda H., Niwa T., Kondo M., Hasegawa Y., Kume H., Noda Y. Influence of leukotriene pathway polymorphisms on clinical responses to montelukast in Japanese patients with asthma. J. Clin. Pharm. Ther. 2013; 37 (1): 112–6.
  24. Tcheurekdjian H., Via M., De Giacomo A., Corvol H., Eng C., Thyne S., Chapela R., Rodriguez-Cintron W., Rodriguez-Santana J.R., Avila P.C., Burchard E.G. Genetics of Asthma in Latino Americans Study. ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos. J. Allergy Clin. Immunol. 2010; 126 (4): 853–8.
  25. Sampson A.P., Siddiqui S., Buchanan D., Howarth P., Holgate S., Holloway J., Holloway, J.W., Sayers I. Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax. 2000; 55 (2): 28–31.
  26. Asano K., Shiomi T., Hasegawa N., Nakamura H., Kudo H., Matsuzaki T., Hakuno H., Fukunaga K., Suzuki Y., Kanazawa M., Yamaguchi K. Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics and Genomics. 2002; 12 (7): 565–70.
  27. Lima J.J., Blake K.V., Tantisira K.G., Weiss S.T. Pharmacogenetics of asthma. Curr Opin Pulm Med. 2009; 15 (1): 57–62.
  28. Mokronosova M.A., Ado V.A., Perlamutrov Yu.N. Rol` leykotrienov v patogeneze allergicheskih zabolevaniy: obzor. Immunologiya. 1996; 1: 17–28. [Mokronosova M.A., Ado V.A., Perlamutrov Yu.N. The role of leukotrienes in the pathogenesis of allergic diseases: a review. Immunology. 1996; 1: 17–28 (in Russian)]
  29. Ado V.A., Mokronosova M.A., Perlamutrov Yu.N. Allergiya i leykotrieny: obzor. Klinicheskaya medicina. 1995; 73: 9–12. [Ado V.A., Mokronosova M.A., Perlamutrov Yu.N. Allergy and leukotrienes: a review. Clinical medicine. 1995; 73: 9–12 (in Russian)]
  30. Diamant Z., Grootendorst D., Veselic-Charvat M., Timmers M.C., De Smet M., Leff J.A., Seidenberg B.C., Zwinderman A.H., Peszek I., Sterk P.J. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell in asthma. Clin. Exp. Allergy. 1999; 29 (1): 42–51.
  31. Busse W. The role and contribution of leukotrienes in asthma. Ann Allerg. Asthma Immunol. 1998; 81 (1): 17–26.
  32. Smith J. Leukotrienes in asthma. The potential therapeutic role ofantileukotriene agents. Arch. Intern. Med. 1996; 156 (19): 2181–9.
  33. Al-Shemari H., Bossé Y., Hudson T. J., Cabaluna M., Duval M., Lemire M., Vallee-Smedja S., Frenkiel S., Desrosiers M. Influence of leukotriene gene polymorphisms on chronic rhinosinusitis. BMC Med. Genet. 2008; 26: 21.
  34. Park J.S., Chang H.S., Park C.S., Lee J.H., Lee Y.M., Choi J.H., Park S., Kim L.H., Park B.L., Choi Y.H., Shin H.D. Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet. Genomics. 2005; 15: 483–92.
  35. Kang M.J., Kwon J.W., Kim B.J., Yu J., Choi W.A., Shin Y.J., Hong S.J. Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma. J. Hum. Genet. 2011; 56: 284–9.
  36. Dahlin A., Litonjua A., Lima J. J., Tamari M., Kubo M., Irvin C. G., Peters S.P., Tantisira K.G. Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in asthma. PLoS ONE. 2015; 10 (6).
  37. Dahlin A., Litonjua A., Irvin C.G., Peters S.P., Lima J.J., Kubo M., Tamari M., Tantisira K.G. Genome-wide association study of leukotriene modifier response in asthma. Pharmacogenomics J. 2016; 16: 151–7.
  38. Chiba M., Xu X., Nishime J.A., Balani S.K., Lin, J.H. Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist, in humans. Drug Metab Dispos. 1997; 25: 1022–31.
  39. Kassahun K., Skordos K., McIntosh I., Slaughter D., Doss G.A., Baillie T.A., Yost G.S. Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic alpha, beta unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme. Chem Res Toxicol. 2005; 18: 1427–37.
  40. Filppula A.M., Laitila J., Neuvonen P.J., Backman J.T. Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. Drug Metab Dispos. 2011; 39: 904–11.
  41. VandenBrink B.M., Foti R.S., Rock D.A., Wienkers L.C., Wahlstrom J.L. Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate. Drug Metab Dispos. 2011; 39: 1546–54.
  42. Adkins J.C., Brogden R.N. Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drugs. 1998; 55: 121–44.
  43. Dekhuijzen P.N., Koopmans P.P. Pharmacokinetic profile of zafirlukast. Clin. Pharmacokinet. 2002; 41: 105–14.
  44. Walsky R.L., Obach R.S., Gaman E.A., Gleeson J.P., Proctor W.R. Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos. 2005; 33: 413–8.
  45. Jaakkola T., Laitila J., Neuvonen P.J., Backman J.T. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol. 2006; 99: 44–51.
  46. Kajosaari L.I., Niemi M., Neuvonen M., Laitila J., Neuvonen P.J., Backman J.T. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin. Pharmacol. Ther. 2005; 78: 388–99.
  47. Kim K.A., Park P.W., Kim K.R., Park J.Y. 2007. Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br. J. Clin. Pharmacol. 2007; 63: 339–45.
  48. Lee H.J., Kim Y.H., Kim S.H., Lee C.M., Yang A.Y., Jang C.G., Lee S.Y., Bae J.W., Choi C.I. Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast. Arch Pharm Res. 2016; 39 (7): 1013.
  49. Mougey E.B., Feng H., Castro M., Irvin C.G., Lima J.J. Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics. 2009; 19 (2): 129–38.
  50. Tapaninen T., Karonen T., Backman J.T., Neuvonen P.J., Niemi M. SLCO2B1 c.935G>A SNP has no effect on the pharmacokinetics of montelukast and aliskiren. Pharmacogenetics and genomics 2012 Nov