PREVALENCE OF CYP2C19 GENETIC POLYMORPHISMS IN RUSSIAN PATIENTS WITH PEPTIC ULCERS TREATED WITH PROTON PUMP INHIBITORS

DOI: https://doi.org/None

N.P. Denisenko (1,2), D.A. Sychev (1,2), Zh.M. Sizova (2), R.E. Kazakov (3), A.V. Grachev (4) 1 -Russian Medical Academy of Post-GraduateEducation, Barrikadnaya str., 2/1, Moscow, 125993, Russian Federation; 2 -I.M. Sechenov First Moscow State Medical University, Trubetskaya str., 8/2, Moscow, 119991, Russian Federation; 3 -Center for clinical pharmacology of the Scientificcentre for Expertise of medicinal products, Yauzskaya str., 11/6, Moscow, 110924, Russian Federation; 4 -SM-Clinic, Cosmonaut Volkov st., 9/2, Moscow, 125130, Russian Federation

Introduction. Cytochrome P-450 2C19 is the main isoenzyme responsible for the metabolism of proton pump inhibitors, the main group of drugs for treating stomach and duodenal ulcer. There are genetic differences that affect the activity of this enzyme: there are allelic variants of CYP2C19, which can be associated with poor metabolism of proton pump inhibitors, and recently the data on variants with increased enzymic activity were found. The aim of the study – to find the prevalence of genotypes for СYP2C19*2, СYP2C19*3, СYP2C19*17allelic variants in Russian population. Methods. 971 patients with stomach and duodenal ulcer were included into the study (age range: 15 to 88 years, 428 male, 543 female). Genotypes were identified with the use of Real-Time PCR. Results. 317 patients (32,65%) out of 971 were shown to be CYP2C19*1/*1 genotype carriers (extensive metabolizers), 386 (39,75%) had CYP2C19*1/*17 or CYP2C19*17/*17 genotype (rapid metabolizers). 251 people (25,85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. 17 participants (1,75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. Allelic frequencies were the following: CYP2C19*2 – 0,14, CYP2C19*3 – 0,006, CYP2C19*17 – 0,274. Conclusion. In Russian patients with acid-related diseases there is a high prevalence of genotypes related to improper pharmacological response to proton pump inhibitors.
Keywords: 
CYP2C19, proton pump inhibitors, Russian
Список литературы: 
  1. Hagymási K., Müllner K., Herszényi L., Tulassay Z. Update on the pharmacogenomics of proton pump inhibitors. Pharmacogenomics. 2011; 12 (6): 873–88.
  2. Furuta T., Shirai N., Sugimoto M., Ohashi K., Ishizaki T. Pharmacogenomics of proton pump inhibitors. Pharmacogenomics. 2004; 5 (2): 181–202.
  3. Chaudhry A.S., Kochhar R., Kohli K.K. Genetic polymorphism of CYP2C19 & therapeutic response to proton pump inhibitors. Indian J MedRes. 2008; 127 (6): 521–30.
  4. Furuta T., Shirai N., Takashima M., Xiao F., Hanai H., Nakagawa K., Sugimura H., Ohashi K., Ishizaki T. Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics. 2001; 11 (4): 341–8.
  5. Furuta T., Shirai N., Takashima M., Xiao F., Hanai H., Sugimura H., Ohashi K., Ishizaki T., Kaneko E. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin. Pharmacol. Ther. 2001; 69 (3): 158–68.
  6. Gawrońska-Szklarz B., Siuda A., Kurzawski M., Bielicki D., Marlicz W., Droździk M. Effects of CYP2C19, MDR1, and interleukin 1-B gene variants on the eradication rate of Helicobacter pylori infection by triple therapy with pantoprazole, amoxicillin, and metronidazole. Eur. J. Clin. Pharmacol. 2010; 66 (7): 681–7.
  7. Yang J.C., Lin C.J. CYP2C19 genotypes in the pharmacokinetics /pharmacodynamics of proton pump inhibitor-based therapy of Helicobacter pylori infection. Expert Opin. Drug Metab. Toxicol. 2010; 6 (1): 29–41.
  8. Baldwin R.M., Ohlsson S., Pedersen R.S., Mwinyi J., Ingelman-Sundberg M., Eliasson E., Bertilsson L. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br. J. Clin. Pharmacol. 2008; 65 (5): 767–74.
  9. Furuta T., Sugimoto M., Shirai N. Individualized therapy for gastroesophageal reflux disease: potential impact of pharmacogenetic testing based on CYP2C19. Mol. Diagn Ther. 2012; 16 (4): 223–34.
  10. Gardiner S.J., Begg E.J. Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice. Pharmacol. Rev. 2006; 58: 521–90.
  11. Jinda S., Nakatani K., Nishioka J., Yasuda K., Soya Y., Hayashi A., Wada H., Nobori T. Personalized treatment in the eradication therapy for Helicobacter pylori. Int. J. Mol. Med. 2011; 27 (2): 255–61.
  12. Gaikovitch E.A., Cascorbi I., Mrozikiewicz P.M., Brockmöller J., Frötschl R., Köpke K., Gerloff T., Chernov J.N., Roots I. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur. J. Clin. Pharmacol. 2003; 59: 303–12.
  13. Lebedeva E.G., Maev I.V., Belyj P.A. Vlijanie polimorfizma gena CYP2C19 na jeffektivnost’ ispol’zovanija ingibitorov protonnoj pompy v lechenii gastrojezofageal’noj refljuksnoj bolezni. Lechashhij vrach. 2011; 7: 93–5.
  14. Herman D., Dolzan V., Breskvar K. Genetic polymorphism of cytochromes P450 2C9 and 2C19 in Slovenian population. Zdrav. Vestn. 2003; 72: 347–51.
  15. Scordo M.G., Caputi A.P., D’Arrigo C., Fava G., Spina E. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol. Res. 2004; 50 (2): 195–200.
  16. Arvanitidis K., Ragia G., Iordanidou M., Kyriaki S., Xanthi A., Tavridou A., Manolopoulos V.G. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Clin. Pharmacol. 2007; 21 (4): 419–26.
  17. Bozina N., Granić P., Lalić Z., Tramisak I., Lovrić M., Stavljenić-Rukavina A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J. 2003; 44 (4): 425–8.
  18. Tamminga W.J., Wemer J., Oosterhuis B., de Zeeuw R.A., de Leij L.F., Jonkman J.H. The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers. Eur. J. Clin. Pharmacol. 2001; 57 (10): 717–22.
  19. Brockmöller J., Rost K.L., Gross D., Schenkel A., Roots I. Phenotyping of CYP2C19 with enantiospecific HPLC-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 G-->A-splice site mutation. Pharmacogenetics. 1995; 5 (2): 80–8.
  20. Sim S., Risinger C., Dahl M.L., Aklillu E., Christensen M., Bertilsson L., Ingelman-Sundberg M. Sommon novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin. Pharmacol. Ther. 2006; 79 (1): 103–13.