Abstract
Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.
Highlights
Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and epileptogenesis is the development of a neuronal network in which spontaneous seizures occur [1,2,3]
Since the metabolism of antiepileptic drugs (AEDs) represents the prominent pathway of elimination (Table 1), both in qualitative and quantitative terms, the inter-individual capacity of hepatic metabolism of AEDs is the primary cause of the variability in the pharmacokinetics, and even in the pharmacodynamics of the AEDs [18,19]
The CYP2C19 genotypes were not associated with the tolerance. These results suggest that CYP2C19 polymorphisms are associated with the clinical efficacy of clobazam therapy, but that they are not associated with tolerance to the drug [35]
Summary
Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and epileptogenesis is the development of a neuronal network in which spontaneous seizures occur [1,2,3]. Pharmacogenetics concerns the link between the genetic constitution of an individual and his/her reaction to drugs [10,13,14,15,16]. This discipline promises the possibility of one day choosing the right drug for any individual, i.e., effective treatment without major adverse effects at an effective dose, only a few of isolated examples has been available in clinical practice [10,15,16]. In a review published in 2009, the impact of genetic variations in drugmetabolizing enzymes was concluded to have a limited clinical impact on AED therapy [7]. Future directions for the AED dose-adjustment according to both genetic and non-genetic factors affecting the pharmacokinetics of AEDs are discussed
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