title: CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects.
abstract: BACKGROUND
  Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects.
  
  
  METHODS
  Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile.
  
  
  CONCLUSIONS
  There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies.
authors.affiliation: C. Mondino National Neurological Institute , Pavia , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Franco
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005838:Genotype; D006801:Humans; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C9; adverse effects; drug metabolism; epilepsy; genetic polymorphism; pharmacogenomics; phenytoin