Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2023.02.002
Brazilian Journal of Anesthesiology
Original Investigation

CYP2D6 isoenzyme and ABCB1 gene polymorphisms associated with postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy: a randomized trial

Polimorfismos da isoenzima CYP2D6 e do gene ABCB1 associados a náuseas e vômitos pós-operatórios em mulheres submetidas à colecistectomia laparoscópica: um ensaio randomizado

Angela Henrique Silva Ribeiro, Estêvão Luiz Carvalho Braga, Nathalia de Araújo Gouveia Ferreira, Beni Olej, Nubia Verçosa, Leonardo dos Santos Antunes, Ismar Lima Cavalcanti

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Abstract

Introduction

Postoperative nausea and vomiting is still a common complication. Serotonin receptor antagonists are commonly used in clinical practice for antiemetic prophylaxis. Interindividual variations in drug response, including single nucleotide polymorphisms, are related to pharmacokinetic and pharmacodynamic changes in these drugs and may lead to a poor therapeutic response. This study aimed to evaluate the influence of CYP2D6 isoenzyme and ABCB1 gene polymorphisms on the frequency of postoperative nausea and vomiting with the use of ondansetron or palonosetron.  

Methods

A randomized, double-blind clinical trial including 82 women aged 60 years or over undergoing laparoscopic cholecystectomy was conducted. Patients were randomized to receive either ondansetron or palonosetron for postoperative nausea and vomiting prophylaxis. DNA was extracted from saliva. Genetic polymorphisms were analyzed by real-time polymerase chain reaction. The following polymorphisms were analyzed: rs3892097 C/T, rs1128503 A/G, rs16947 A/G, rs1065852 A/G, rs1045642 A/G, rs2032582 C/A, and rs20325821 C/A. 

Results

Overall, vomiting, and severe nausea occurred in 22.5% and 57.5% of patients, respectively. In the palonosetron group, patients with the GG genotype (rs16947 A/G) experienced more severe nausea (p = 0.043). In the ondansetron group, patients with the AA genotype (rs16947 A/G) presented mild nausea (p = 0.034), and those with the AA genotype (rs1065852 A/G) experienced more vomiting (p = 0.034).

Conclusion

A low antiemetic response was observed with ondansetron in the presence of the AA genotype (rs16947 A/G) and the AA genotype (rs1065852 A/G), and a low therapeutic response was found with palonosetron in the presence of the GG genotype (rs16947 A/G) in laparoscopic cholecystectomy.

Register

ClinicalTrials.gov.

Keywords

Antiemetics; Genetic polymorphism; Laparoscopic cholecystectomy; Ondansetron; Palonosetron; Postoperative nausea and vomiting

Resumo

Introdução

Náuseas e vômitos pós-operatórios ainda são uma complicação comum. Os antagonistas dos receptores de serotonina são comumente usados na prática clínica para profilaxia antiemética. Variações interindividuais na resposta aos medicamentos, incluindo polimorfismos de nucleotídeo único, estão relacionadas a alterações farmacocinéticas e farmacodinâmicas nesses medicamentos e podem levar a uma resposta terapêutica deficiente. Este estudo teve como objetivo avaliar a influência da isoenzima CYP2D6 e dos polimorfismos do gene ABCB1 na frequência de náuseas e vômitos pós-operatórios com uso de ondansetrona ou palonossetrom.

Métodos

Foi realizado um ensaio clínico randomizado, duplo-cego, incluindo 82 mulheres com 60 anos ou mais submetidas à colecistectomia laparoscópica. Os pacientes foram randomizados para receber ondansetrona ou palonossetrom para profilaxia de náuseas e vômitos no pós-operatório. O DNA foi extraído da saliva. Os polimorfismos genéticos foram analisados por reação em cadeia da polimerase em tempo real. Foram analisados os seguintes polimorfismos: rs3892097 C/T, rs1128503 A/G, rs16947 A/G, rs1065852 A/G, rs1045642 A/G, rs2032582 C/A e rs20325821 C/A.

Resultados

No geral, vômitos e náuseas graves ocorreram em 22,5% e 57,5% dos pacientes, respectivamente. No grupo palonossetrom, os pacientes com genótipo GG (rs16947 A/G) apresentaram náuseas mais intensas (p = 0,043). No grupo ondansetrona, pacientes com genótipo AA (rs16947 A/G) apresentaram náusea leve (p = 0,034), e aqueles com genótipo AA (rs1065852 A/G) apresentaram mais vômitos (p = 0,034).

Conclusão

Uma baixa resposta antiemética foi observada com ondansetrona na presença do genótipo AA (rs16947 A/G) e do genótipo AA (rs1065852 A/G), e uma baixa resposta terapêutica foi encontrada com palonossetrom na presença do genótipo GG (rs16947 A/G) em colecistectomia laparoscópica.

Palavras-chave

Antieméticos; Polimorfismo genético; Colecistectomia laparoscópica; Ondansetrona; Palonossetrom; Náuseas e vômitos pós-operatórios

References

1. White PF, O’Hara JF, Roberson CR, Wender RH, Candiotti KA, Group P-OS. The impact of current antiemetic practices on patient outcomes: a prospective study on high-risk patients. Anesth Analg. 2008;107(2):452−8.

2. Gan T, Sloan F, Dear Gde L, El-Moalem HE, Lubarsky DA. How much are patients willing to pay to avoid postoperative nausea and vomiting? Anesth Analg. 2001;92(2):393−400.

3. Chatterjee S, Rudra A, Sengupta S. Current concepts in the management of postoperative nausea and vomiting. Anesthesiol Res Pract. 2011;2011:748031.

4. Bala I, Bharti N, Murugesan S, Gupta R. Comparison of palonosetron with palonosetron-dexamethasone combination for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Minerva Anestesiol. 2014;80(7):779−84.

5. Apfel CC, Roewer N. Risk assessment of postoperative nausea and vomiting. Int Anesthesiol Clin. 2003;41(4):13−32.

6. Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118(1):85−113.

7. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350 (24):2441−51. 8. Gntech [Internet]. [cited 2022 Feb 5]. Available from: https:// gntech.med.br/.

9. Nagele P. Perioperative genomics. Best Pract Res Clin Anaesthesiol. 2011;25(4):549−55.

10. Singh KP, Dhruva AA, Flowers E, Kober KM, Miaskowski C. A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting. Crit Rev Oncol Hematol. 2018;121:51−61.

11. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001;286(18):2270−9.

12. Borst P, Schinkel AH. P-glycoprotein ABCB1: a major player in drug handling by mammals. J Clin Invest. 2013;123(10): 4131−3.

13. Babaoglu MO, Bayar B, Aynacioglu AS, Kerb R, Abali H, Celik I, et al. Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists. Clin Pharmacol Ther. 2005;78(6):619−26.

14. Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006;19(6):606−11.

15. Klenke S, Frey UH. Genetic variability in postoperative nausea and vomiting: A systematic review. Eur J Anaesthesiol. 2020;37 (11):959−68.

16. Lopez-Morales P, Flores-Funes D, Sanchez-Migallon EG, LironRuiz RJ, Aguayo-Albasini JL. Genetic factors associated with postoperative nausea and vomiting: a systematic review. J Gastrointest Surg. 2018;22(9):1645−51.

17. Perwitasari DA, Wessels JA, van der Straaten RJ, Baak-Pablo RF, Mustofa M, Hakimi M, et al. Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy. Jpn J Clin Oncol. 2011;41(10):1168−76.

18. Carvalho Braga EL, Figueiredo NV, Barrucand L, Cavalcanti IL. Use of palonosetron and ondansetron in the prophylaxis of postoperative nausea and vomiting in women 60 years of age or older undergoing laparoscopic cholecystectomy: A randomised double-blind study. Eur J Anaesthesiol. 2019;36(3):241−2.

19. Laha B, Hazra A, Mallick S. Evaluation of antiemetic effect of intravenous palonosetron versus intravenous ondansetron in laparoscopic cholecystectomy: a randomized controlled trial. Indian J Pharmacol. 2013;45(1):24−9.

20. Kim MS, Lee JR, Choi EM, Kim EH, Choi SH. Association of 5- HT3B receptor gene polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting. Yonsei Med J. 2015;56(5):1415−20.

21. Song JW, Shim JK, Choi SH, Soh S, Jang J, Kwak YL. Comparison of ramosetron and palonosetron for preventing nausea and vomiting after spinal surgery: association with ABCB1 polymorphisms. J Neurosurg Anesthesiol. 2017;29(4):406−14.

22. Choi EM, Lee MG, Lee SH, Choi KW, Choi SH. Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting. Anaesthesia. 2010;65(10):996 −1000.

23. He H, Yin JY, Xu YJ, Li X, Zhang Y, Liu ZG, et al. Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. Clin Ther. 2014;36 (8):1242−52. e2.

24. Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg. 2006;102(6):1884−98.

25. Stamer UM, Schmutz M, Wen T, Banz V, Lippuner C, Zhang L, et al. A serotonin transporter polymorphism is associated with postoperative nausea and vomiting: An observational study in two different patient cohorts. Eur J Anaesthesiol. 2019;36 (8):566−74.

26. Mitsunaga Y, Kubota T, Ishiguro A, Yamada Y, Sasaki H, Chiba K, et al. Frequent occurrence of CYP2D6*10 duplication allele in a Japanese population. Mutat Res. 2002;505(1-2):83−5.

27. Klenke S, de Vries GJ, Schiefer L, Seyffert N, Bachmann HS, Peters J, et al. CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective. Br J Anaesth. 2018;121(1):58 −65.

28. Sim SC, Ingelman-Sundberg M. Update on allele nomenclature for human cytochromes P450 and the Human Cytochrome P450 Allele (CYP-allele) nomenclature database. Methods Mol Biol. 2013;987:251−9.

29. Braga ELC, Vercosa N, Cavalcanti IL. Comparative study between fosaprepitant and palonosetron in the prophylaxis of postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy: prospective, randomized and double-blind study. Front Pharmacol. 2022;13:915347.

30. Janicki PK, Vealey R, Liu J, Escajeda J, Postula M, Welker K. Genome-wide Association study using pooled DNA to identify candidate markers mediating susceptibility to postoperative nausea and vomiting. Anesthesiology. 2011;115(1): 54−64.


Submitted date:
09/11/2022

Accepted date:
02/13/2023

642ed5b4a95395501658ca63 rba Articles
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