CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects

Abstract

Introduction: 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.

Keywords:

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

Declaration of interest

E Perucca has received research grants from the EU, the Italian Medicines Agency, the Italian Ministry of Health and the Italian Ministry for Education, University and Research, and has received speaker’s or consultancy fees grants from Eisai, GlaxoSmithKline, GW Pharma, UCB Pharma and Viropharma. V Franco is a former employee of Eisai s.r.l. Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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