An update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects

Expert Opin Drug Metab Toxicol. 2020 Aug;16(8):723-734. doi: 10.1080/17425255.2020.1780209. Epub 2020 Jul 16.


Introduction Phenytoin is a frequently used drug treatment for epilepsy. Genetic polymorphisms in the metabolism of phenytoin, particularly CYP2C9, are strongly associated with increased plasma concentrations and can result in toxicity. Human leukocyte antigen (HLA) alleles are well-known genetic predictors of certain antiepileptic drug-associated severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recent pharmacogenomic studies show genetic polymorphisms in CYP2C9, as well as HLA alleles, are significantly associated with phenytoin-related SCAR. Areas covered Updated pharmacogenomic information of CYP2C9 variants and HLA alleles involved in phenytoin-associated cutaneous adverse drug reactions (cADRs) are discussed in this article. Expert opinion CYP2C9*3 has been identified as the most significant genetic variant associated with increased phenytoin concentrations and adverse events. Recent pharmacogenomic findings reveal that CYP2C9*3 and HLA alleles, i.e. HLA-B*15:02, HLA-B*13:01, and HLA-B*51:01, are important genetic variants in the occurrence of phenytoin-induced cADRs or SCAR. A phenotype- and population-specific multigene panel can be used before prescribing to predict phenytoin-induced cADRs and further guide optimal dose selection.

Keywords: Adverse drug reaction (ADR); CYP2C9; Stevens-Johnson syndrome (SJS); human leukocyte antigen (HLA); pharmacogenomics; phenytoin; toxic epidermal necrolysis (TEN).

Publication types

  • Review

MeSH terms

  • Anticonvulsants / administration & dosage*
  • Anticonvulsants / adverse effects
  • Anticonvulsants / pharmacokinetics
  • Cytochrome P-450 CYP2C9 / genetics
  • Epilepsy / drug therapy*
  • HLA-B Antigens / genetics
  • Humans
  • Pharmacogenetics
  • Phenytoin / administration & dosage*
  • Phenytoin / adverse effects
  • Phenytoin / pharmacokinetics
  • Polymorphism, Genetic


  • Anticonvulsants
  • HLA-B Antigens
  • Phenytoin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9