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Contributions of CYP2C9/CYP2C19 Genotypes and Drug Interaction to the Phenytoin Treatment in the Korean Epileptic Patients in the Clinical Setting

  • Lee, Soo-Youn (Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine and Samsung Medical Center) ;
  • Lee, Seung-Tae (Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine and Samsung Medical Center) ;
  • Kim, Jong-Won (Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine and Samsung Medical Center)
  • Published : 2007.05.31

Abstract

We examined the contribution of CYP2C9 and CYP2C19 genotypes and drug interactions to the phenytoin metabolism among 97 Korean epileptic patients to determine if pharmacogenetic testing could be utilized in routine clinical practice. The CYP2C9 polymorphism is a wellknown major genetic factor responsible for phenytoin metabolism. The CYP219 polymorphism, with a high incidence of variant alleles, has a minor influence on phenytoin treated Koran patients. Using a multiple regression model for evaluation of the CYP2C9 and CYP2C19 genotypes, together with other non-genetic variables, we explained 39.6% of the variance in serum phenytoin levels. Incorporation of genotyping for CYP2C9 and CYP2C19 into a clinical practice may be of some help in the determination of phenytoin dosage. However, because concurrent drug treatment is common in patients taking phenytoin and many environmental factors are likely to play a role in drug metabolism, these factors may overwhelm the relevance of CYP polymorphisms in the clinical setting. Further investigations with an approach to dose assessment that includes comprehensive interpretation of both pharmacogenetic and pharmacokinetic data along with understanding of the mechanism of drug interactions in dosage adjustment is warranted.

Keywords

References

  1. Anderson, G. D. (1998) A mechanistic approach to antiepileptic drug interactions. Ann. Pharmacother. 32, 554-563. https://doi.org/10.1345/aph.17332
  2. Carter, B. L., Garnett, W. R., Pellock, J. M., Stratton, M. A. and Howell, J. R. (1981) Effect of antacids on phenytoin bioavailability. Ther. Drug Monit. 3, 333-340. https://doi.org/10.1097/00007691-198104000-00003
  3. Frigo, G. M., Lecchini, S., Caravaggi, M., Gatti, G., Tonini, M., D'Angelo, L., Perucca, E. and Crema, A. (1983) Reduction of phenytoin clearance caused by cimetidine. Eur. J. Clin. Pharmacol. 25 , 135-137. https://doi.org/10.1007/BF00544030
  4. Goldstein, J. A., Ishizaki, T., Chiba, K., de Morais, S. M., Bell, D., Krahn, P. M. and Evans, D. A. (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7, 59-64. https://doi.org/10.1097/00008571-199702000-00008
  5. Haselberger, M. B., Freedman, L. S. and Tolbert, S. (1997) Elevated serum phenytoin concentrations associated with coadministration of sertraline. J. Clin. Psychopharmacol. 17, 107-109. https://doi.org/10.1097/00004714-199704000-00008
  6. Horsmans, Y., Van den Berge, V., Bouckaert, A. and Desager, J. P. (1997) Phenytoin hydroxylation in a healthy Caucasian population: bimodal distribution of hydroxyphenytoin urinary excretion. Pharmacol. Toxicol. 81, 276-279.
  7. Hung, C. C., Lin, C. J., Chen, C. C., Chang, C. J. and Liou, H. H. (2004) Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther. Drug Monit. 26, 534-540. https://doi.org/10.1097/00007691-200410000-00012
  8. Mamiya, K., Ieiri, I., Shimamoto, J., Yukawa, E., Imai, J., Ninomiya, H., Yamada, H., Otsubo, K., Higuchi, S. and Tashiro, N. (1998) The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 39, 1317-1323. https://doi.org/10.1111/j.1528-1157.1998.tb01330.x
  9. Mamiya, K., Kojima, K., Yukawa, E., Higuchi, S., Ieiri, I., Ninomiya, H. and Tashiro, N. (2001) Phenytoin intoxication induced by fluvoxamine. Ther. Drug Monit. 23 , 75-77. https://doi.org/10.1097/00007691-200102000-00014
  10. Nasu, K., Kubota, T. and Ishizaki, T. (1997) Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 7, 405-409. https://doi.org/10.1097/00008571-199710000-00011
  11. Odani, A., Hashimoto, Y., Otsuki, Y., Uwai, Y., Hattori, H., Furusho, K. and Inui, K. (1997) Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin. Pharmacol. Ther. 62, 287-292. https://doi.org/10.1016/S0009-9236(97)90031-X
  12. Riva, R., Albani, F., Contin, M. and Baruzzi, A. (1996) Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations. Clin. Pharmacokinet. 31, 470-493. https://doi.org/10.2165/00003088-199631060-00005
  13. Schmider, J., Greenblatt, D. J., von Moltke, L. L., Karsov, D. and Shader, R. I. (1997) Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin phydroxylation. Br. J. Clin. Pharmacol. 44, 495-498. https://doi.org/10.1046/j.1365-2125.1997.00601.x
  14. Soga, Y., Nishimura, F., Ohtsuka, Y., Araki, H., Iwamoto, Y., Naruishi, H., Shiomi, N., Kobayashi, Y., Takashiba, S., Shimizu, K., Gomita, Y. and Oka, E. (2004) CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects. Life Sci. 74, 827-834. https://doi.org/10.1016/j.lfs.2003.07.018
  15. Spina, E., Pisani, F. and Perucca, E. (1996) Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin. Pharmacokinet. 31, 198-214. https://doi.org/10.2165/00003088-199631030-00004
  16. van der Weide, J., Steijns, L. S., van Weelden, M. J. and de Haan, K. (2001) The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 11, 287-291. https://doi.org/10.1097/00008571-200106000-00002
  17. Watanabe, M., Iwahashi, K., Kugoh, T. and Suwaki, H. (1998) The relationship between phenytoin pharmacokinetics and the CYP2C19 genotype in Japanese epileptic patients. Clin. Neuropharmacol. 21, 122-126.
  18. Wedlund, P. J. (2000) The CYP2C19 enzyme polymorphism. Pharmacology 61, 174-183. https://doi.org/10.1159/000028398
  19. 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. (2001) Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br. J. Clin. Pharmacol. 51, 277-280. https://doi.org/10.1046/j.1365-2125.2001.00340.x

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