Lviv clinical bulletin 2020, 1(29): 34-38

https://doi.org/10.25040/lkv2020.01.034

CYP2C9 Polymorphism Study in Patients with Acute Back Pain and its Impact on the Effectiveness of Treatment with the Non-Steroidal Anti-Inflammatory Drugs

Posted onAuthorAdminЗалишити коментар / Leave a comment

I. Maslova1, N. Mykhailovska2, T. Slobodin2

1MOTOR SICH medical facility, Zaporizhzhia

2Shupyk National Medical Academy of Postgraduate Education, Kyiv

Introduction. Genetic factors can generate different variants of physiological responses to non-steroidal anti­inflammatory drugs (NSAIDs) – from the complete ineffectiveness of medicines to the appearance of adverse reactions. The presence of mutant alleles of the gene CYP2C9, which codes for a basic enzyme in the biotransformation of NSAIDs in the liver, cytochrome P4502C9, leads to reduced activity and slow metabolism of NSAIDs, increases the risk of side effects, overdose. Therefore, the study of influence of CYP2C9 gene polymorphism in our population and its influence on the effectiveness of treatment of NSAIDs in acute back pain is important.

The aim of the study. To investigate the polymorphism of CYP2C9 in patients with acute back pain and its impact on the effectiveness of their treatment with the non-steroidal anti-inflammatory drugs.

Materials and methods. The study involved 93 patients (60 women (64.5 %) and 33 men (35.5 per cent) aged 45 to 60 years) with acute pain syndrome and aggravation of chronic pain syndrome that were divided into two groups: 53 patients (36 women and 17 men aged 45-60 years) treated with meloxicam 15.0 mg 1 time per day and the comparative group of 40 patients (24 women and 16 men aged 45-60 years) who took celecoxib 200.0 mg/day for 10 days. Evaluation of efficiency was performed before and on the 1st, 10th day of treatment and at 30th, 90th days of observation using Visual Analogue Scale (VAS). All patients underwent a genetic test – the determination of the allelic variants CYP2C9*2 and CYP2C9*3 CYP2C9 gene with polymerase chain reaction (PCR). The data obtained were subject to statistical processing.

Results. For the marker of CYP2C9(Arg144Cys) genotype Arg/Arg was found in 79.6 % of cases, genotype Arg/Cys – 20.4 % of cases, and no representative of the genotype Cys/Cys was found. For the marker of CYP2C9(Ile369Leu) genotype Ile/Ile was found in 87.1 % of cases, the genotype Ile/Leu – 12.9 % of cases and no case of genotype Leu/ Leu was found.

Heterozygotes for CYP2C9(Arg144Cys) and CYP2C9(IIe369Leu) taking meloxicam demonstrated the best rate of pain reduction compared with homozygotes as on the 10-th day of treatment, and on the 90th day of observation, but the difference was not statistically significant.

Heterozygotes for CYP2C9(Arg144Cys) and CYP2C9(IIe369Leu) who took celecoxib had a significantly better dynamics on the 10th day of treatment.

Conclusions. The genotype frequency of the CYP2C9 (Arg144Cys) and CYP2C9 (IIe369Leu) mutant alleles in our population is about 20.0 %. One in five patients with acute low back pain has genotypes with the CYP2C9 (Arg144Cys) and CYP2C9 (IIe369Leu) mutant alleles, which means there is an increased risk of side effects of non-steroidal anti-inflammatory drug treatment.

Relationship between CYP2C9 (Arg144Cys), CYP2C9 (IIe369Leu) genotypes and statistically significant better response to 10-day celecoxib treatment has been established, indicating greater efficacy of celecoxib in patients with slow metabolism of medicine, and a higher risk of side effects, especially when celecoxib is given in combination with other drugs metabolized by CYP2C9.

References

  1. Bochkov NP. Clinical genetics. 2nd ed. Moscow: Geotar-Med; 2002. 447 p. (Russian)
  2. Kukes VG. Clinical pharmacology. 3rd ed. Moscow: Geotar-Med; 2006. 944 p. (Russian)
  3. Leonova MV, Alimova EE. Pharmacogenetics of non-steroidal anti-inflammatory drugs: existing problems for clinical practice. Meditsinsky Sovet. 2018;21:204-209. (Russian).
    https://doi.org/10.21518/2079-701X-2018-21-204-209
  4. Shvartz GJ. Modern non-steroidal antiinflammatory drugs. 2nd ed. Moscow: Reapharm; 2004. 95 p. (Russian)
  5. Agiindez JAG, Garcia-Martin E, Martinez C. Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009;5(6):607-620. https://doi.org/10.1517/17425250902970998
  6. Baron R, Binder A, Wasner G. Neuropathic pain-diagnosis, pathophysiological mechanisms and treatment. Lancet Neurol.2010;9:807-819. https://doi.org/10.1016/S1474-4422(10)70143-5
  7. Evans WE, Pharm D, McLeod HL. Pharmacogenomics – Drug Disposition, Drug Targets, and Side Effects. N Engl J Med. 2003;348:538-549. https://doi.org/10.1056/NEJMra020526
  8. Figueras A, Estany-Gestal A, Aguirre C, Ruiz B, Vidal X, Carvajal A et al. CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study. Pharmacogenet Genomics. 2016;26(2):66-73. https://doi.org/10.1097/FPC.0000000000000186
  9. Kim SH, Kim DH, Byeon JY, Kim YH, Kim DH, Lim HJ et al. Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite. Arch Pharm Res. 2017;40(3):382-390. https://doi.org/10.1007/s12272-016-0861-2
  10. Lazarou, J, Pomeranz, BH, Corey PN. Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA. 1998;279(15):1200-1205. https://doi.org/10.1001/jama.279.15.1200
  11. Martinez C, Blanco G, Ladero JM, Garcia-Martin E, Diaz-Rubio M, Agiindez JA еt al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol. 2004;141(2):205-208. https://doi.org/10.1038/sj.bjp.0705623
  12. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by pharmacogenetics of safety and efficacy of non-steroidal anti-inflammatory drugs: A review. Current Drug Metabolism. 2014;15:326-343. https://doi.org/10.2174/1389200215666140202214454
  13. Sosters C, Gargallo C, Arroyo M, Lanas A. Adverse effects of non-steroidal antiinflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010;24(2):21-32. https://doi.org/10.1016/j.bpg.2009.11.005
  14. Wyatt JE., Pettit WL, Harirforoosh S. Pharmacogenetics of nonsteroidal antiinflammatory drugs. Pharmacogenomics J. 2012;12:462-467. https://doi.org/10.1038/tpj.2012.40