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CYP2C19 Polymorphism in Korean patients on warfarin therapy

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Abstract

This study was designed to assess the effect of CYP2C19 polymorphism on warfarin dosage requirements and bleeding complications in the Korean population. Patients were placed into one of four groups according to the dose of warfarin they received and the presence of bleeding complications: regular dose control, regular dose bleeding, low dose control, and low dose bleeding. Genotyping for CYP2C19*2 and CYP2C19*3 was performed by the restriction fragment length polymorphism method for each patient and each study group. The measured internal normalized ratio (INR) in each dose group was similar even though the administered dosage was significantly different. A total of 66 patients were evaluated for CYP2C19 polymorphism. Among them 25 patients (37.9%) were homozygous wild type. Four patients (6.1%) had heterozygous mutations at both loci. Others had mutations on either the CYP2C19*2 or *3 locus. Higher genetic variation was observed in CYP2C19*2 than in CYP2C19*3 among Korean patients on warfarin therapy. Our data suggested that there is a higher incidence of bleeding complications in patients who have a higher allele frequency of CYP2C19. It was also revealed that the distribution of CYP2C19 polymorphism among Asian populations is more similar than of the distribution among Caucasian populations.

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References

  1. Aithal, G. P., Day, C. P., Kesteven, P. J. L, and Daly, A. K., Association of polymorphism in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.Lancet, 353, 717–719 (1999).

  2. Bertilsson, L, Lou, Y. Q., Du, Y. L., Liu, Y, Kuang, T. Y, Liao, X. M., Wang, K. Y, Reviriego, J., Iselius, L., and Sjoeqvist, F., Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin.Clin. Pharmacol. Then, 51, 388–397(1992).

  3. Chan, E., McLachlan, A. J., Pegg, M., MacKay, A. D., Cole, R. B., and Rowland, M., Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac- warfarin.Br. J. Clin. Pharmacol., 37, 563–569 (1994).

  4. de Morais, S. M., Wilkinson, G R., Blaisdell, J., Meyer, U. A, Nakamura, K., and Goldstein, J. A., Identification and a new genetic defect responsible for the polymorphism of (S)- mephenytoin metabolism in Japanese.Mol. Pharm., 46, 594–98 (1994a).

  5. de Morais, S. M., Wilkinson, G R., Blaisdell, J., Nakamura, K., Meyer, U. A., and Goldstein, J. A., The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans.J. Biol. Chem., 269, 15419–15422 (1994b).

  6. Desta, Z., Zhao, X., Shin, J. G, and Flockhart, D. A, Clinical significance of the cytochrome P450 2C19 genetic polymorphism.Clin. Pharmacokinet, 41, 913–958 (2002).

  7. Fukasawa, T., Yasui-Furukori, N., Suzuki, A., Inoue, Y, Tateishi, T., and Otani, K., Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.Eur. J. Clin. Pharmacol., 61, 791–795 (2005).

  8. Furuya, H., Femandez-Salguero, P., Gregory, W., Taber, H., Steward, A., Gonzalez, F., and Idle, J. R., Genetic polymor- phism of CYP2C9 and its effects on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy.Pharmacogenetics, 5, 389–392 (1995).

  9. Goldstein, J. A. and Blaisdell, J., Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism.Methods Enzymol., 272, 210–218(1996).

  10. Goldstein, J. A., Clincal relevance of genetic polymorphism in the human CYP2C subfamily.Br. J. Clin. Pharmacol., 52, 349–55(2001).

  11. Goldstein, J. A., Faletto, M. B., Romkes-Sparks, M., Sullivan, T., Kitareewan, S., Raucy, J. L, Lasker, J. M., and Ghanayem, B. I., Evidence that CYP2C19 is the major (S)-mephenytoin 4’-hydroxylase in humans.Biochemistry, 33, 1743–1752 (1994).

  12. Henne, K. R., Gaedigk, A., Gupta, G, Leeder, J. S., and Rettie, A. E., Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype.J. Chroma- togr. B Biomed. Sci. Appl., 710,143–148 (1998).

  13. Herrlin, K., Massele, A. Y, Jande, M., Aim, C, Tybring, G, Abdi, Y A., Wennerholm, A., Johansson, I., Dohl, M. L, Bertilsson, L, and Gustafsson, L. L, Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.Clin. Pharmacol. Then, 64,391–401(1998).

  14. Higashi, M. K., Veenstra, D.L., Kondo, L. M., Wittkowsky, A. K., Srinouanprachanh, S. L, Farin, F. M., and Rettie, A. E., Association between CYP2C9 gentic variants and anticoagul- ation-related outcomes during warfarin therapy.JAMA, 287, 1690–1698(2002).

  15. Hirsh, J., Dalen, J. E., Anderson, D. R., Poller, L, Bussey, H., Ansell, J., and Deykin, D., Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.Chest, 114, 445S-69S (1998).

  16. Inomata, S., Nagashima, A., Itagaki, F., Homma, M., Nishimura, M., Osaka, Y, Okuyana, K., Tanaka, E., Nakanura, T., Kohdo, Y, Naito, S., Miyabe, J., and Toyooka, H., CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.Clin. Pharmacol. Then, 78, 647–655 (2005).

  17. Ishizawa, Y, Yasui-Furukori, N., Takahata, T., Sasaki, M., and Tateishi, T., The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics.Clin. Pharmacokinet. 44, 1179–1189 (2005).

  18. James, A. H., Britt, R. P., Risking, C. L, and Thompson, S. G, Factors affecting the maintenance dose of warfarin.J. Clin. Pathoi, 45, 704–706(1992).

  19. Kaminsky, L. S. and Zhang, Z.Y, Human P450 metabolism of warfarin.Pharmacol. Ther., 73, 67–74 (1994).

  20. Kimura, M., leri, I., Mamiya, K., Urae, A., and Higuchi, S., Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population.Ther. Drug Monit, 20, 243–247(1998).

  21. Landefeld, C. S. and Beyth, R. J., Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention.Am. J. Med., 95, 315–28 (1993).

  22. Lee, S., Kim, J.-M., Chung, C.-S., Cho, K. J., and Kim, J. H., Polymorphism in CYP2C9 as a non-critical factor of warfarin dosage adjustments in Korean patients.Arch. Pharm. Res., 26, 967–972 (2003).

  23. Levine, M. N., Raskob, G, Landefeld, S., and Kearon, C., Hemorrhagic complications of anticoagulant treatment.Chest, 119, 108S-121S(2001).

  24. Niu, C. Y., Luo, J. Y., and Hao, Z. M., Genetic polymorphism analysis of cytochrome P4502C19 in Chinese Uigur and Han populations.Chinese J. Dig.estive Dis., 5, 76–80 (2004).

  25. Roh, H. K., Kim, P. S., Lee, D. H., Tybring, G, Safar, M., Park, C. S., Seensalu, R., and Bertilsson, L., Omeprazole treatment of Korean patients: effects on gastric pH and gastrin release in relation to CYP2C19 geno- and phenotypes.Basic Clin. Pharmacol. Toxicol., 95, 112–119 (2004).

  26. Roh, H. K., Dahl, M. L, Tybring, G, Yamada, H., Cha, Y. N., and Bertilsson, L., CYP2C19 genotype and phenotype determined by omeprazole in a Korean population.Pharmacogenetics, 6, 547–551 (1996).

  27. Rosemary, J., Adithan, C, Padmaja, N., Shashindran, C. H., Gerard, N., and Krishnamoorthy, R., The effect of the CYP2C19 genotype on the gydroxylation index of omeprazole in south Indians.Eur. J. Clin. Pharmacol., 61, 19–23(2005).

  28. Scordo, M. G, Pengo, V, Spina, E., Dahl, M. L, Gusella, M., and Padrini, R., Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance.Clin. Pharmacol. Then, 72, 702–710 (2002).

  29. Wallin, R., Sane, D. C, and Hutson, S. M., Vitamin K 2,3- epoxide reductase and the vitamin K-dependent gamma-carboxylation system.Thromb. Res., 108, 221–226 (2002).

  30. Wang, P. P., Beaune, P., Kaminsky, L. S., Dannan, G A., Kadlubar, F. F., Larrey, D., and Guvengerich, F. P., Purification and characterization of six cytochrome P-450 isozymes from human liver microsomes.Biochemistry, 22, 5375–5383(1983).

  31. Xie, H. G, Prasad, H. C, Kim, R. B., and Stein, C. M., CYP2C9 allelic variants: ethnic distribution and functional significance.Adv. Drug Deliv. Rev., 54, 1257–1270 (2002).

  32. Yoon, Y R., Shon, J. H., Kim, M. K., Lim, Y C, Lee, H. R., Park, J. Y, Cha, I. J., and Shin, J. G, Frequency of cytochrome P450 2C9 mutant alleles in a Korean population.Br. J. Clin. Phramacol., 51, 277–280 (2001).

  33. Zackrisson, A. L, Holmgren, P., Gladh, A. B., Ahlner, J., and Lindblom, B., Fatal intoxication cases: cytochrome P4502D6 and 2C19 genotype distribution.Eur. J. Clin. Pharmacol., 60, 547–552 (2004).

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Correspondence to Sukhyang Lee or Hyun Jin Hwang or Jae-Moon Kim or Chin-Sang Chung or Jeong Hee Kim.

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Lee, S., Hwang, H.J., Kim, J. et al. CYP2C19 Polymorphism in Korean patients on warfarin therapy. Arch Pharm Res 30, 344 (2007). https://doi.org/10.1007/BF02977616

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Key words

  • CYP2C19
  • Polymorphism
  • Warfarin