Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
권호 표지

Phenytoin Toxicity in a Korean Patient Homozygous for $CYP2C9^{\ast}3$

  • Lee, Soo-Youn (Departments of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine) ;
  • Kim, Jong-Won (Departments of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine) ;
  • Kim, Jong-Soo (Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Published : 2006.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

We report a case of phenytoin toxicity due to impaired drug metabolism in a patient homozygous for $CYP2C9^{\ast}3$. A 46-year-old woman was taking phenytoin to prevent postoperative seizures. She attained high serum phenytoin levels at the standard doses (300 mg/day) and developed symptoms of phenytoin toxicity including blurred vision, nausea and headache. The patient was treated with reduced doses of phenytoin and then phenytoin therapy was finally discontinued. Genotyping for CYP2C9 revealed that this patient had a homozygous genotype, $CYP2C9^{\ast}3/^{\ast}3$. This is the first Korean case of phenytoin toxicity with homozygous $CYP2C9^{\ast}3$. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of phenytoin.

Keywords

References

  1. Levine, M. & Chang, T. Therapeutic drug monitoring of phenytoin. Rationale and current status. Clin. Pharmacokinet. 19, 341-358 (1990) https://doi.org/10.2165/00003088-199019050-00001
  2. Richens, A. Clinical pharmacokinetics of phenytoin. Clin. Pharmacokinet. 4, 153-169 (1979) https://doi.org/10.2165/00003088-197904030-00001
  3. Bajpai, M., Roskos, L.K., Shen, D.D. & Levy, R.H. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab. Dispos. 24, 1401-1403 (1996)
  4. Mamiya, K. et al. 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 (1998) https://doi.org/10.1111/j.1528-1157.1998.tb01330.x
  5. Miners, J.O. & Birkett, D.J. Cytochrome P4502C9:an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol. 45, 525-538 (1998) https://doi.org/10.1046/j.1365-2125.1998.00721.x
  6. Giancarlo, G.M. et al. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur. J. Clin. Pharmacol. 57, 31-36 (2001) https://doi.org/10.1007/s002280100268
  7. Horsmans, Y., Van den Berge, V., Bouckaert, A. & Desager, J.P. Phenytoin hydroxylation in a healthy Caucasian population: bimodal distribution of hydroxyphenytoin urinary excretion. Pharmacol. Toxicol. 81, 276-279 (1997)
  8. Goldstein, J.A. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br. J. Clin. Pharmacol. 52, 349-355 (2001) https://doi.org/10.1046/j.0306-5251.2001.01499.x
  9. Kirchheiner, J. & Brockmoller, J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin. Pharmacol. Ther. 77, 1-16 (2005) https://doi.org/10.1016/j.clpt.2004.08.009
  10. Hung, C.C. et al. Dosage recommendation of pheny-toin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther. Drug Monit. 26, 534-540 (2004) https://doi.org/10.1097/00007691-200410000-00012
  11. van der Weide, J., Steijns, L.S., van Weelden, M.J. & de Haan, K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 11, 287-291 (2001) https://doi.org/10.1097/00008571-200106000-00002
  12. Rettie, A.E., Haining, R.L., Bajpai, M. & Levy, R.H. A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin. Epilepsy Res. 35, 253-255 (1999) https://doi.org/10.1016/S0920-1211(99)00017-0
  13. Soga, Y. et al. CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects. Life Sci. 74, 827-834 (2004) https://doi.org/10.1016/j.lfs.2003.07.018
  14. Odani, A. et al. 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 (1997) https://doi.org/10.1016/S0009-9236(97)90031-X
  15. Yoon, Y.R. et al. Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br. J. Clin. Pharmacol. 51, 277-280 (2001) https://doi.org/10.1046/j.1365-2125.2001.00340.x
  16. Brandolese, R. et al. Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clin. Pharmacol. Ther. 70, 391-394 (2001)
  17. Lardizabal, D.V., Luders, H.O., Hovinga, C.A. & Bourgeois, B.F. Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 62, 161; author reply 161 (2004) https://doi.org/10.1212/WNL.62.1.161
  18. Ninomiya, H. et al. Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. Ther. Drug Monit. 22, 230-232 (2000) https://doi.org/10.1097/00007691-200004000-00016
  19. Aynacioglu, A.S. et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br. J. Clin. Pharmacol. 48, 409-415 (1999) https://doi.org/10.1046/j.1365-2125.1999.00012.x