Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms

The Pharmacogenomics Journal volume 13, pages 359–361 (2013)Cite this article

Subjects

Abstract

Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg−1), intravenous diazepam (0.3 mg kg−1), and intravenous phenytoin with an initial-loading dose of 15 mg kg−1. However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l−1; normal range: 10–20 mg l−1), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Odani A, Hashimoto Y, Otsuki Y, Uwai Y, Hattori H, Furusho K et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 1997; 62: 287–292.

    Article  CAS  PubMed  Google Scholar 

  2. Goldstein JA . Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, LLerena A . CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 2003; 59: 221–225.

    Article  CAS  PubMed  Google Scholar 

  4. Van der Weide J, Steijns LSW, van Weelden MJM, de Haan K . The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 2001; 11: 287–291.

    Article  CAS  PubMed  Google Scholar 

  5. Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J . Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 2010; 69: 222–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mamiya K, Ieiri I, Shimamoto J, Yukawa E, Imai J, Ninomiya H, Yamada H 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 1998; 39: 1317–1323.

    Article  CAS  PubMed  Google Scholar 

  7. Odani A, Hashimoto Y, Otsuki Y, Uwai Y, Hattori H, Furusho K et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 1997; 62: 287–292.

    Article  CAS  PubMed  Google Scholar 

  8. Luna-Tortós C, Fedrowitz M, Löscher W . Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology 2008; 55: 1364–1375.

    Article  PubMed  Google Scholar 

  9. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. NEJM 2003; 348: 1442–1448.

    Article  CAS  PubMed  Google Scholar 

  10. Hung CC, Chen CC, Lin CJ, Liou HH . Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Pharmacogenet Genomics 2008; 18: 390–402.

    Article  CAS  PubMed  Google Scholar 

  11. Kerb R, Aynacioglu AS, Brockmöller J, Schlagenhaufer R, Bauer S, Szekeres T et al. The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for Phenytoin plasma levels. Pharmacogenomics J 2001; 1: 204–210.

    Article  CAS  PubMed  Google Scholar 

  12. Hennessy S, Leonard CE, Freeman CP, Metlay JP, Chu X, Strom BL et al. CYP2C9, CYP2C19, and ABCB1 genotype and hospitalization for phenytoin toxicity. J Clin Pharmacol 2009; 49: 1483–1487.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Brandolese R, Scordo MG, Spina E, Gusella M, Padrini R . Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clin Pharmacol Ther 2001; 70: 391–394.

    CAS  PubMed  Google Scholar 

  14. Criterio G, Nobili A, Airoldi L, Pastorelli R, Patruno A . Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 2003; 60: 1395–1396.

    Article  Google Scholar 

  15. Ramasamy K, Narayan SK, Chanolean S, Chandrasekaran A . Severe phenytoin toxicity in a CYP2C9*3*3 homozygous mutant from India. Neurol India 2007; 55: 408–409.

    Article  PubMed  Google Scholar 

  16. McCluggage LK, Voils SA, Bullock MR . Phenytoin toxicity due to genetic polymorphism. Neurocrit Care 2009; 10: 222–224.

    Article  PubMed  Google Scholar 

  17. Kesavan R, Narayan SK, Adithan C . Influence of CYP2C9 and CYP2C19 genetic polymorphisms on phenytoin-induced neurological toxicity in Indian epileptic patients. Eur J Clin Pharmacol 2010; 66: 689–696.

    Article  CAS  PubMed  Google Scholar 

  18. Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci USA 2005; 102: 5507–5512.

    Article  CAS  PubMed  Google Scholar 

  19. Liu H, Delgado M, Forman LJ, Eggers CM, Montoya JL . Simultaneous determination of carbamazepine, phenytoin, phenobarbital, primidone and their principal metabolites by high-performance liquid chromatography with photodiode-array detection. J Chromatogr 1993; 616: 105–115.

    Article  CAS  PubMed  Google Scholar 

  20. Ninomiya H, Mamiya K, Matsuo S, Ieiri I, Higuchi S, Tashiro N . Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. Ther Drug Monit 2000; 22: 230–232.

    Article  CAS  PubMed  Google Scholar 

  21. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–3478.

    Article  CAS  PubMed  Google Scholar 

  22. Blain PG, Mucklow JC, Bacon CJ, Rawlins MD . Pharmacokinetics of phenytoin in children. Br J Clin Pharmacol 1981; 12: 659–661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gerber N, Wagner JG . Explanation of dose-dependent decline of diphenylhydantoin plasma levels by fitting to the integrated form of the Michaelis-Menten equation. Res Commun Chem Pathol Pharmacol 1972; 3: 455–466.

    CAS  PubMed  Google Scholar 

  24. Soskin DP, Kane AJ, Stern TA . Phenytoin toxicity secondary to an oxcarbazepine-phenytoin 2C19 interaction. Psychosomatics 2010; 51: 532–535.

    PubMed  Google Scholar 

  25. Sallas WM, Milosavljev S, D'souza J, Hossain M . Pharmacokinetic drug interactions in children taking oxcarbazepine. Clin Pharmacol Ther 2003; 74: 138–149.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Spanish Ministry of Science, Innovation and Technology (ISCIII)-FIS and EU FEDER Grants PI10/02010 and CP06/00030 (P. Dorado) and PRIS Extremadura, Consejería de Sanidad y Dependencia, FundeSalud (PRIS11051). This study was coordinated in the networks CIBERSAM and CAIBER, which are initiatives of ISCIII (Spain).

Author information

Author notes

  1. P Dorado and E López-Torres: These authors contributed equally to this work.

Authors and Affiliations

  1. CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz, Spain,

    P Dorado, E M Peñas-LLedó & A LLerena

  2. Neuropediatric Unit, Materno-Infantil Carlos Haya Hospital, Malaga, Spain

    E López-Torres & J Martínez-Antón

  3. CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

    A LLerena

Authors
  1. P Dorado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E López-Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E M Peñas-LLedó
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Martínez-Antón
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A LLerena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Dorado.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dorado, P., López-Torres, E., Peñas-LLedó, E. et al. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms. Pharmacogenomics J 13, 359–361 (2013). https://doi.org/10.1038/tpj.2012.19

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2012.19

Keywords

This article is cited by

Search

Advanced search

Quick links