Evaluation of the association of SNP in carboxylesterase enzyme (CES1) with pharmacokinetic and adverse effects of capecitabine in breast and colorectal cancer patients

DOI: 10.26650/IstanbulJPharm.2019.19018Capecitabine is an oral prodrug and converted to 5-fluorouracil using three-step enzymatic pathways which include carboxylesterase (CES).  Interindividual differences in the activities of drug-metabolizing enzymes may affect efficacy and toxicity. The aim of this study is to evaluate the association of Single nucleotide polymorphisms (SNP) in CES1 with the pharmacokinetic and adverse effects of capecitabine. Plasma samples were obtained from 7 breast and colorectal cancer patients who were treated with capecitabine-based chemotherapy (1000-1250 mg/m2) at 0.5, 1, 2, 3 and 4 hours following drug administration on their first day of the first cycle. The plasma concentrations of the capecitabine were determined by using a high-pressure liquid chromatography-UV detector. SNP (rs8192950) was genotyped using the reverse transcription-polymerase chain reaction. Patients were found to have heterozygote (57%), wild (29%), and mutant (14%) distributions of genotypes (p=0.909). The mean plasma area under the curve (AUC0-4h) was 4.60±2.25 µg.h/mL, and maximum plasma concentration (Cmax) was 3.19±2.5 µg/mL. There were no statistically significant differences between genotypes and AUC values (p=0.2236) and the most frequently observed side effects were diarrhea (p=0.1028), asthenia (p=0.6456), anemia (p=0.6456), emesis (p=0.3499). This is the first study evaluating an association of genetic variation in CES1 (rs8192950) with pharmacokinetic and adverse effects of capecitabine. Therefore, additional study in larger groups of patients is required to support our study. Cite this article as: Kurtan Yüksel M, Öztürk D, Öztaş E, Özhan G, Altanlar Türker A, Korkmaz T, Okyar A, Pala Kara Z (2019). Evaluation of the association of SNP in carboxylesterase enzyme (CES1) with pharmacokinetic and adverse effects of capecitabine in breast and colorectal cancer patients. Istanbul J Pharm 49 (2): 64-69.

___

  • Daniele G, Gallo M, Piccirillo C, Giordano P, D’Alessio A, Del Giudice A, La Porta ML, Perrone F, Normanno N, De Luca A (2013). Pharmacokinetic evaluation of capecitabine in breast cancer. Expert Opin Drug Metab Toxicol 9: 225-235. Farkouh A, Ettlinger D, Schueller J, Georgopoulos A, Scheithauer W, Czejka M (2010). A rapid and simple HPLC assay for quantification of capecitabine for drug monitoring purposes. Anticancer Res 30: 5207-5211. Geshi E, Kimura T, Yoshimura M, Suzuki H, Koba S, Sakai T, Saito T, Koga A, Muramatsu M, Katagiri T (2005). A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity. Hypertens Res 28: 719-725. Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiader CR. (2017) Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity. Clin Pharmacol Ther 102: 796-804. Kim SR, Nakamura T, Saito Y, Sai K, Nakajima T, Saito H, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J (2003). Twelve novel single nucleotide polymorphisms in the CES2 gene encoding human carboxylesterase 2 (hCE-2). Drug Metab Pharmacokinet 18: 327-332. Lam SW, Guchelaar HJ, Boven E (2016). The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22. Langmann T, Becker A, Aslanidis C, Notka F, Ullrich H, Schwer H, Schmitz G (1997). Structural organization and characterization of the promoter region of a human carboxylesterase gene. Biochim Biophys Acta 1350: 65-74. Lewis JP, Horenstein RB, Ryan K, O’Connell JR, Gibson Q, Mitchell BD, Tanner K, Chai S, Bliden KP, Tantry US, Peer CJ, Figg WD, Spencer SD, Pacanowski MA, Gurbel PA, Shuldiner AR (2013). The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet Genomics 23: 1-8. Marsha S, Xiao M, Yu J, Ahluwalia R, Minton M, Freimuth RR, Kwok PY, McLeod HL (2004). Pharmacogenomic assessment of carboxylesterases 1 and 2. Genomics 84: 661-668. Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P, Siegbahn A, Syvanen AC, Wadelius C, Wadelius M, Zimdahl-Gelling H, Yusuf S, Wallentin L (2013). Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding. Circulation 127: 1404-1412. Pellicer M, García-González X, García MI, Robles L, Grávalos C, García-Alfonso P, Pachón V, Longo F, Martínez V, Blanco C, Iglesias I, Sanjurjo M, López-Fernández LA (2017). Identification of new SNPs associated with severe toxicity to capecitabine. Pharmacol Res 120: 133-137. Reigner B, Blesch K, Weidekamm E (2001). Clinical Pharmacokinetics of Capecitabine. Clin Pharmacokinet 40: 85-104. Ribelles N, Lopez-Siles J, Sanchez A, Gonzalez E, Sanchez MJ, Carabantes F (2008). A Carboxylesterase 2 Gene Polymorphism as Predictor of Capecitabine on Response and Time to Progression. Curr Drug Metab 9: 336-343. Rudek MA, Connolly RM, Hoskins JM, Garrett-Mayer E, Jeter SC, Armstrong DK, Fetting JH, Stearns V, Wright LA, Zhao M, Watkins SP Jr, McLeod HL, Davidson NE, Wolff AC (2013) Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer. Breast Cancer Res Treat 139: 135-143. Siegel RL, Miller KD, Jemal A (2019). Cancer statistics, 2019. CA Cancer J Clin 69: 7-34. Tarkiainen EK, Backman JT, Neuvonen M, Neuvonen PJ, Schwab M, Niemi M (2012). Carboxylesterase 1 polymorphism impairs oseltamivir bioactivation in humans. Clin Pharmacol Ther 92: 68-71. Tarkiainen EK, Tornio A, Holmberg MT, Launiainen T, Neuvonen PJ, Backman JT, Niemi M (2015). Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol 80: 1131-1138. TC Ministry of Health General Directorate of Public Health (2018) Turkey Cancer Statistics 2015. Ankara: TC Ministry of Health General Directorate of Public Health. Access 26.10.2018, https://hsgm.saglik.gov.tr/depo/birimler/kanser-db/istatistik/Turkiye_Kanser_Istatistikleri_2015.pdf. Thorn CF, Marsh S, Carrillo MW, McLeod HL, Klein TE, Altman RB (2011). PharmGKB summary: fluoropyrimidine pathways. Pharmacogenet Genomics 21: 237-242. Turkish Medicines and Medical Devices Agency (TİTCK) (2002, May) Xeloda Roche 500 mg Summary of Product Characteristics. Access 20.11.2017. Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L (2018). Human carboxylesterases: a comprehensive review. Acta Pharm Sin B 8: 699-712. Xiao FY, Luo JQ, Liu M, Chen BL, Cao S, Liu ZQ, Zhou HH, Zhou G, Zhang W(2017). Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients. Sci Rep 7: 7244. Zhao Z, Li X, Sun S, Mei S, Ma N, Miao Z, Zhao M, Peng S (2016). Impact of genetic polymorphisms related to clopidogrel or acetylsalicylic acid pharmacology on clinical outcome in Chinese patients with symptomatic extracranial or intracranial stenosis. Eur J Clin Pharmacol 72: 1195-1204.