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Genetic polymorphism of NAT2 metabolizing enzymes on phenytoin pharmacokinetics in Indian epileptic patients

M Murali1, T Manjari, B Madhuri

  • 1Department of Neurobiochemistry, AIIMS, New Delhi, India.

CNS Neuroscience & Therapeutics
|January 25, 2012
PubMed
Abstract

Insights

The NAT2*5A genetic polymorphism significantly impacts phenytoin pharmacokinetics and toxicity in epileptic patients. Poor metabolizers exhibit longer phenytoin half-life and reduced clearance, increasing toxicity risk.

Area of Science:

  • Pharmacogenomics
  • Clinical Pharmacology
  • Neuroscience

Background:

  • The antiepileptic drug phenytoin is crucial for managing epilepsy.
  • Individual variability in phenytoin response and toxicity is a clinical challenge.
  • Genetic variations in drug-metabolizing enzymes, like NAT2, can influence drug pharmacokinetics.

Purpose of the Study:

  • To investigate the influence of NAT2 polymorphisms on phenytoin pharmacokinetics in epileptic patients experiencing toxicity.
  • To identify specific NAT2 variants associated with phenytoin-induced toxicity.

Main Methods:

  • Genotyping for NAT2 polymorphisms (NAT2*5A, NAT2*5C, NAT2*7, NAT2*6) using PCR-RFLP in 50 epileptic patients with phenytoin toxicity and 50 controls.
  • Quantification of phenytoin plasma levels via reversed-phase HPLC.
  • Estimation of pharmacokinetic parameters (AUC, Cmax, tmax, t1/2) using non-compartmental analysis.

Main Results:

  • Significant genotypic and allelic association found between NAT2*5A (481C>T) and NAT2*5C (803A>G) polymorphisms and phenytoin toxicity.
  • Poor metabolizers with NAT2*5A exhibited a prolonged elimination half-life (35.3 h) and reduced clearance (468 mL/h) compared to intermediate and extensive metabolizers.
  • Phenytoin toxicity was significantly linked to specific NAT2 genetic variations.

Conclusions:

  • The NAT2*5A genetic polymorphism plays a critical role in determining steady-state phenytoin concentrations.
  • These findings highlight the impact of NAT2 variations on phenytoin-related toxicity in epileptic individuals.
  • Pharmacogenetic profiling of NAT2 may aid in personalized phenytoin dosing to mitigate toxicity.

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