The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs

  title={The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs},
  author={Ulrich Klotz},
  journal={Clinical Pharmacokinetics},
  • U. Klotz
  • Published 2007
  • Biology, Medicine
  • Clinical Pharmacokinetics
Several different factors, including pharmacogenetics, contribute to inter-individual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of… 

[Pharmacogenetics and antiepileptic drug metabolism: implication of genetic variants in cytochromes P450].

The identification of interindividual variability in the response to AEDs may allow the personalized treatment with the aim of maximize the efficiency and minimize risk, regardless of the clinical variability and adverse effects could be manifest in a minority of the patients.

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

The state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies is summarized and future directions for the dose-adjustment of A ED are discussed.

Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs

This review summarizes the pharmacogenetics (PGx) of AEDs and provides a model-based approach that enables the integration of PGx data with other relevant sources of variability, such as demographic characteristics and co-medications.

The clinical impact of cytochrome P450 polymorphisms on anti-epileptic drug therapy

It is reported that the CYP2C19-deficient genotype is associated with the serum concentration of an active metabolite of clobazam, N-desmethylclobazem, and with the clinical efficacy of clOBazam therapy.

Farmacogenética e antiepilépticos (farmacologia das drogas antiepilépticas: da teoria à prática)

The optimized use of antiepileptic drugs to treatment of epilepsy is usually compromised by lack of therapeutic response, unexpected side effects and unexplained variations of antIEpileptics plasma levels, which could explain some of these problems.

Study of CYP2C9 and CYP2C19 polymorphisms in a Romanian epilepsy population.

The distribution of CYP2C9 and CYP 2C19 polymorphisms in a Romanian epileptic population is determined and a comparison between the population with epilepsy and a healthy population is made, regarding the distribution of the major mutant alleles that determine the poor-metabolizer status.

The clinical impact of pharmacogenetics on the treatment of epilepsy

This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target, drug transport, drug metabolizing, and human leucocyte antigen (HLA) proteins.

The effect of polymorphic metabolism enzymes on serum phenytoin level

The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients.

CYP3A5∗3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents

The study failed to corroborate association between polymorphism CYP3A5∗3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy and do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies.



Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens and, because of its narrow therapeutic range, genotyping of CYPs in addition to CYP1C9 may be needed to optimise the dosage of phenytoin.

Clinical Consequences of Cytochrome P450 2C9 Polymorphisms

Challenges and opportunities in the application of pharmacogenetics to antiepileptic drug therapy.

In order for AED treatment guidelines to begin to have clinical impact, standards specific to the conduct of future AED studies must be established and the need for accurate epilepsy classification, appropriate AED selection and clear and objective assessment outcome measures must be understood.

Clinically relevant drug interactions with antiepileptic drugs.

  • E. Perucca
  • Medicine, Biology
    British journal of clinical pharmacology
  • 2006
Some patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs), and pharmacodynamic interactions involving AEDs have not been well characterized, but their understanding is important for a more rational approach to combination therapy.

Influence of the CYP2C9 AND CYP2C19 polymorphisms on phenytoin hydroxylation in healthy individuals from south India.

CYP2C9*2 and *3 mutant alleles caused decreased hydroxylation of phenytoin in vivo, whereas the mutant allels of CYP2C19 played only a minor role in the metabolism of Pheny toin in subjects of the study.

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

Evidence is provided of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine.


It was determined that CYP2C9 plays a relatively minor role in the overall clearance of sulindac, naproxen, ketoprofen, diclofenac, rofecoxib, and etoricoxib and CYP1C9 genotype would have no clinically meaningful impact on the pharmacokinetics of these drugs.

CYP2C19 polymorphism effect on phenobarbitone

It appears that the disposition of PB is mediated in part by this enzyme, and the estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient.

Geographical/Interracial Differences in Polymorphic Drug Oxidation

Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians.