CYP2C9 polymorphisms and phenytoin metabolism: Implications for adverse effects

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Abstract

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.Areas covered: Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile.Expert opinion: 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.

Original languageEnglish
Pages (from-to)1269-1279
Number of pages11
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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Phenytoin
Polymorphism
Metabolism
Pharmacokinetics
Genetic Polymorphisms
Drug interactions
Safety
Cytochrome P-450 CYP2C9
Expert Testimony
Enzymes
Cost effectiveness
Drug Interactions
Anticonvulsants
Cost-Benefit Analysis
Genotype
Prospective Studies
Skin
Testing

Keywords

  • Adverse effects
  • CYP2C9
  • drug metabolism
  • epilepsy
  • genetic polymorphism
  • pharmacogenomics
  • phenytoin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

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abstract = "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.Areas covered: Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile.Expert opinion: 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.",
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