The Study of CYP2C19 Genetic Polymorphisms in Thai Patients Taking Stable Doses of Warfarin

Main Article Content

Nitsupa Wattanachai
Sutthida Kaewmoongkun
Pattarapong Makarawate
Nontaya Nakkam
Burabha Pussadhamma
Chaiyasith Wongvipaporn
Songsak Kiatchoosakun
Suda Vannaprasaht
Wichittra Tassaneeyakul

Abstract

CYP2C19 is one of the metabolizing enzymes involved in the metabolism of both R- and S-warfarin. The aim of this study was to investigate the association of CYP2C19 polymorphisms on the variability of stable warfarin doses in Thai patients. A total of 254 Thai patients with stable warfarin doses were enrolled in the study. Demographics and clinical data e.g. age, body mass index, and concomitant medications, were recorded. The single nucleotide polymorphisms in the CYP2C19*2 and CYP2C19*3 were detected from gDNA using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while CYP2C19*17 was detected by using TaqManÒ allelic discrimination assay. The results showed that there were no significant differences in the mean stable warfarin doses after adjustment for confounding factors among those of four CYP2C19 metabolizer statuses including the extensive metabolizers (CYP2C19*1/*1 or CYP2C19*2/*17             or CYP2C19*3/*17), and the intermediate metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3 genotypes), the poor metabolizers (CYP2C19*2/*2 or CYP2C19*2/*3 genotypes), and the rapid metabolizers (CYP2C19 *1/*17 genotype) (p > 0.05). In conclusion, the genetic polymorphisms of drug metabolizing enzyme CYP2C19 were not associated with the stable warfarin doses in Thai patients. In addition, CYP2C19 genotypes may not be a useful predictor of warfarin dose adjustments in clinical practice. 

Downloads

Download data is not yet available.

Article Details

Section
Research Articles

References

1. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001 Jan;119(1 Suppl):8S-21S.
2. O'Reilly RA. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther. 1974 Aug;16(2):348-54.
3. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Biochem Pharmacol. 1997 Dec 1;54(11):1195-203.
4. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J. 2007 Apr;7(2):99-111.
5. Flockhart DA, O'Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008 Feb;10(2):139-50.
6. Bourgeois S, Jorgensen A, Zhang EJ, Hanson A, Gillman MS, Bumpstead S, et al. A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome Med. 2016 Jan 6;8(1):2.
7. Wattanachai N, Kaewmoongkun S, Pussadhamma B, Makarawate P, Wongvipaporn C, Kiatchoosakun S, et al. The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients. Eur J Clin Pharmacol. 2017 Aug;73(8):973-80.
8. Kim SY, Kang JY, Hartman JH, Park SH, Jones DR, Yun CH, et al. Metabolism of R- and S-warfarin by CYP2C19 into four hydroxywarfarins. Drug Metab Lett. 2012 Sep 1;6(3):157-64.
9. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002; 41(12):913-58.
10. Sukasem C, Tunthong R, Chamnanphon M, Santon S, Jantararoungtong T, Koomdee N, et al. CYP2C19 polymorphisms in the Thai population and the clinical response to clopidogrel in patients with atherothrombotic-risk factors. Pharmgenomics Pers Med. 2013 Aug 22;6:85-91.
11. Tassaneeyakul W, Mahatthanatrakul W, Niwatananun K, Na-Bangchang K, Tawalee A, Krikreangsak N, et al. CYP2C19 genetic polymorphism in Thai, Burmese and Karen populations. Drug Metab Pharmacokinet. 2006 Aug;21(4): 286-90.
12. Uno T, Sugimoto K, Sugawara K, Tateishi T. The effect of CYP2C19 genotypes on the pharmacokinetics of warfarin enantiomers. J Clin Pharm Ther. 2008 Feb;33(1):67-73.
13. Zhang H, Ma K, Liu W, Yang F, Liu J, Zhou H. Impact of CYP2C19 gene polymorphism on warfarin maintenance doses in patients with non-valvular atrial fibrillation. Gene. 2016 Oct 10;591(1):80-4.
14. Khalighi K, Cheng G, Mirabbasi S, Khalighi B, Wu Y, Fan W. Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy. J Thromb Thrombolysis. 2017 Jan;43(1):124-9.
15. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther. 2002 Dec;72(6):702-10.
16. Lee S, Hwang HJ, Kim JM, Chung CS, Kim JH. CYP2C19 polymorphism in Korean patients on warfarin therapy. Arch Pharm Res. 2007 Mar;30(3):344-9.
17. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006 Jan;79(1):103-13.
18. Chang M, Soderberg MM, Scordo MG, Tybring G, Dahl ML. CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy. Eur J Clin Pharmacol. 2015 Apr;71(4): 433-9.
19. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013 Apr;138(1):103-41.
20. Gaikwad T, Ghosh K, Avery P, Kamali F, Shetty S. Warfarin dose model for the prediction of stable maintenance dose in Indian patients. Clin Appl Thromb Hemost. 2018 Mar;24(2):353-359.

Most read articles by the same author(s)

1 2 > >>