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Gastroenterologie
a hepatologie

Gastroenterology and Hepatology

Gastroent Hepatol 2018; 72(4): 320–328. doi:10.14735/amgh2018320.

Personalized therapy in patients with gastroesophageal reflux disease – methodology of CYP2C19 gene profile’s determination

Petra Bořilová Linhartová1,2, Ladislava Bartošová Orcid.org  1, Adam Křenek3, Ladislav Bartoš4, Jiří Dolina Orcid.org  5, Filip Marek6, Zdeněk Kala Orcid.org  6, Lydie Izakovičová Hollá1,2

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Summary

Introduction: Conservative treatment of gastroesophageal reflux disease (GERD) is currently based on a group of drugs that effectively suppress the secretion of hydrochloric acid in the stomach, so-called proton pump inhibitors (PPI). Although these drugs do not target the cause of the disease, they are considered and accepted as the “gold standard” for the treatment of this disease. The aim of this retrospective study was to map medication of GERD patients in various phases of the disease, to analyze individual variability in the cytochrome P450 (CYP2C19) gene, and to propose an effective method for the simple determination of the gene in GERD patients. Methods: The study included 276 GERD patients with known pharmacological anamnesis who had undergone surgical treatment. The subjects included 94 patients with non-erosive reflux disease, 121 with reflux esophagitis, and 61 with Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC). Genotypes of two polymorphisms in the CYP2C19 gene (*17 rs12248560 and *2 rs4244285) were determined using quantitative polymerase chain reaction. Results: More than 90% patients were treated with PPI (omeprazole/lansoprazole/pantoprazole). Although the prescribed PPI dosing in the studied cohort was consistent with recommendations for maintenance therapy, the patients’ ability to metabolize the active substance was not considered. Carriers of genotype combinations containing the CYP2C9*17 variant, which determines the ultra-rapid metabolizer (UM) phenotype, were less likely to co-occur with the CYP2C19*2 variant, which determines the intermediate or “poor” metabolizer (IM or PM) phenotype, than individuals with the standard functioning CYP2C19 enzyme (p = 0.001). The frequencies of combinations of genotypes (haplogenotypes) and resulting UM/IM/PM phenotypes were 37.3/16.7/1.4% in GERD patients. Conclusion: Prior to initiating PPI pharmacotherapy in GERD patients, determination of CYP2C19 haplogenotypes (CYP2C19*17 and *2 variants) should be performed due to frequent occurence of these variants in population and their functional metabolic significance. We presume that this approach will increase the effectiveness of pharmacotherapy, improve patient quality of life, and very likely help prevent/reduce the risk of the development of more serious conditions, such as BE and EAC. The non-standard ability to metabolize PPI in GERD patients may be one of the indicators for surgical intervention.

Keywords

CYP2C19*17, CYP2C19*2, pharmacogenetics, gastrooesophageal reflux, gene polymorphism, proton pump inhibitors, poor metabolizer, ultra rapid metabolizer

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Literature

1. The Swedish Council on Technology Assess-ment in Health Care. Dyspepsia and gastro-oesophageal reflux. A systematic review. [online]. Available from: https: //www.ncbi.nlm.nih.gov/pubmedhealth/PMH0096647/pdf/PubMedHealth_PMH0096647.pdf.
2. Maes ML, Fixen DR, Linnebur SA. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence. Ther Adv Drug Saf 2017; 8 (9): 273–297. doi: 10.1177/204209 8617715381.
3. Mermelstein J, Mermelstein AC, Chait MM. Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole. Clin Exp Gastroenterol 2016; 9: 163–172. doi: 10.2147/CEG.S91602.
4. Garros A, Mion F, Marjoux S et al. Factors associated with nonresponse to proton pump inhibitors therapy in patients referred for esophageal pH-impedance monitoring. Dis Esophagus 2016; 29 (7): 787–793. doi: 10.1111/dote.12374.
5. Bytzer P, van Zanten SV, Mattsson H et al. Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis – a post hoc analysis of 5796 patients. Aliment Pharmacol Ther 2012; 36 (7): 635–643. doi: 10.1111/apt.12007.
6. Domingues G, Moraes-Filho JP. Noncompliance is an impact factor in the treatment of gastroesophageal reflux disease. Expert Rev Gastroenterol Hepatol 2014; 8 (7): 761–765. doi: 10.1586/17474124.2014.911660.
7. Kawamura O, Hosaka H, Shimoyama Y et al. Evaluation of proton pump inhibitor-resistant nonerosive reflux disease by esophageal manometry and 24-hour esophageal impedance and pH monitoring. Digestion 2015; 91 (1): 19–25. doi: 10.1159/000368766.
8. Yadlapati R, Tye M, Roman S et al. Postprandial high-resolution impedance manometry identifies mechanisms of nonresponse to proton pump inhibitors. Clin Gastroenterol Hepatol 2018; 16 (2): 211–218. doi: 10.1016/j.cgh.2017.09.011.
9. Hagymási K, Müllner K, Herszényi L et al. Update on the pharmacogenomics of proton pump inhibitors. Pharmacogenomics 2011; 12 (6): 873–888. doi: 10.2217/pgs.11.4.
10. Scott SA, Owusu Obeng A, Hulot JS. Antiplatelet drug interactions with proton pump inhibitors. Expert Opin Drug Metab Toxicol 2014; 10 (2): 175–189. doi: 10.1517/17425255.2014.856883.
11. Ogilvie BW, Yerino P, Kazmi F et al. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism – dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel. Drug Metab Dispos 2011; 39 (11): 2020–2033. doi: 10.1124/dmd.111.041293.
12. Furuta T, Shirai N, Sugimoto M et al. Pharmacogenomics of proton pump inhibitors. Pharmacogenomics 2004; 5 (2): 181–202. doi: 10.1517/phgs.5.2.181.27483.
13. Klotz U. Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther 2006; 44 (7): 297–302.
14. Lin YA, Wang H, Gu ZJ et al. Effect of CYP2C19 gene polymorphisms on proton pump inhibitor, amoxicillin, and levofloxacin triple therapy for eradication of Helicobacter pylori. Med Sci Monit 2017; 23: 2701–2707.
15. Rogan PK, Svojanovsky S, Leeder JS. Information theory-based analysis of CYP2C19, CYP2D6 and CYP3A5 splicing mutations. Pharmacogenetics 2003; 13 (4): 207–218. doi: 10.1097/01.fpc.0000054078.64000.de.
16. Food and Drug Administration (FDA). Table of pharmacogenomic biomarkers in drug labeling. [online]. Available from: https: //www.fda.gov/downloads/Drugs/ScienceResearch/UCM 578588.pdf.
17. Hillman L, Yadlapati R, Whitsett M et al.  Review of antireflux procedures for proton pump inhibitor nonresponsive gastroesophageal reflux disease. Dis Esophagus 2017; 30 (9): 1–14. doi: 10.1093/dote/dox054.
18. Suchopár J, Prokeš M. Polypragmazie a lékové interakce. Vnitř Lék 2011; 57 (9): 755–759.
19. Červený P. Inhibitory protonové pumpy: přehled a porovnání základních údajů. Remedia 2009; 9 (6): 432–437.
20. Gregar J, Šimková I, Urbánek K. Lékové interakce inhibitorů protonové pumpy. Klin Farmakol Farm 2011; 25 (4): 188–191.
21. Sugimoto M, Furuta T. Efficacy of esomeprazole in treating acid-related diseases in Japanese populations. Clin Exp Gastroenterol 2012; 5: 49–59. doi: 10.2147/CEG.S23926.
22. Červený P. Rabeprazol. Remedia 2013; 23 (4): 243–247.
23. Li MJ, Li Q, Sun M et al. Comparative effectiveness and acceptability of the FDA-licensed proton pump inhibitors for erosive esophagitis: A PRISMA-compliant network meta-analysis. Medicine (Baltimore) 2017; 96 (39): e8120. doi: 10.1097/MD.0000000000008120.
24. Dean L. Omeprazole therapy and CYP2C19 genotype. In: Pratt V, McLeod H, Dean L (eds). Medical Genetics Summaries.. National Center for Biotechnology Information 2012. [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK100895/.
25. Tang HL, Li Y, Hu YF et al. Effects of CYP2C19 loss-of-function variants on the eradication of H. pylori infection in patientstreated with proton pump inhibitor-based triple therapy regimens: a meta-analysis of randomized clinical trials. PLoS One 2013; 8 (4): e62162. doi: 10.1371/journal.pone.0062162.
26. Serrano D, Torrado S, Torrado-Santiago S et al. The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/-pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments. Curr Drug Metab 2012; 13 (9): 1303–1312.
27. NCBI. dbSNP short genetic variations. Reference SNP (refSNP) Cluster Report: rs4244285. [online]. Available from: https: //www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4244285.
28. Buzková H, Pechandová K, Danzig V et al. Lipid-lowering effect of fluvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population. Med Sci Monit 2012; 18 (8): CR512–CR517. doi: 10.12659/MSM.883272.
29. NCBI. dbSNP short genetic variations.  Reference SNP (refSNP) Cluster Report: rs1224 8560. [online]. Available from: https: //www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs= 12248560.
30. Lewis JP, Stephens SH, Horenstein RB et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost 2013; 11 (9): 1640–1646. doi: 10.1111/jth.12342.
31. Franciosi JP, Mougey EB, Williams A et al.  Association between CYP2C19*17 alleles and pH probe testing outcomes in children with symptomatic gastroesophageal reflux. J Clin Pharmacol 2018; 58 (1): 89–96. doi: 10.1002/jcph.977.
32. Martínek J, Lukáš M. Inhibitory protonové pumpy – up to date. Gastroent Hepatol 2011; 65 (6): 331–342.
33. Furuta T, Sugimoto M, Shirai N et al. CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics 2007; 8 (9): 1199–1210. doi: 10.2217/14622416.8.9.1199.

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