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

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.

Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes

“…Moreover, high UGT2B7 activity shown in donor 3 (Fig. 2c) can contribute to valproate detoxification (Saruwatari et al 2010).…”

“…The proposed strategy allows distinguishing between DILI and non-DILI compounds under chronic exposure as well as identifying the underlying mechanisms of hepatotoxicity. The anticonvulsant agent valproate is known to induce steatosis as well as rare but potentially fatal idiosyncratic hepatotoxicity (Saruwatari et al 2010). Although the mechanisms of liver injury by valproate are still not well understood, the role of mitochondrial dysfunction, including interference with β-oxidation and oxidative stress, derived from enhanced ROS formation and/or altered GSH homeostasis, have been suggested (Silva et al 2008).…”

Therapeutic Drug Monitoring of Antiepileptic Drugs in Real Clinical Practice in Russia

“…TDM allows to objectifying therapeutic drug concentrations to control safety, and identify complementary cases such as inefficiency of therapy and pharmacogenetic problems, requiring medication changing. Thus, pharmacogenetic disorders of AEDs currently being actively studied, because it is thought to be important factor of pharmacokinetic inter-patient variability (especially drug clearance); impetus for such studies was population pharmacokinetic data of AEDs [10].…”

“…At the same time, in 21 (43%) of 48 patients with sub-TC of VPA daily dose was within the average therapeutic (more than 1000 mg/day). It should be noted that in 3 women taking VPA in doses of 500, 1000 and 1500 mg/day as monotherapy the level of Cmax and Cmin remained extremely low -less than 11 mg/l, which may be indicative of pharmacogenetic disorders of VPA metabolism (UGT1A and CYP2C19) [5,9,10]. Among patients with sub-TC of VPA the rate of combined therapy was 39.6%, significantly lower than in the group achieved TC range, so the low concentration could not be explained by pharmacokinetic interactions with other AEDs.…”

The efficacy and safety of valproic acid medications with controlled active ingredient release in adults in real clinical practice from the position of pharmacokinetic and pharmacogenetic approaches

“…1075 А > С; Ile359Leu) [11], у гете-ро-и гомозиготных носителей которых отмечаются более высокие значения максимальной концентрации ВК в кро-ви, периода ее полувыведения, площади под фармакокине-тической кривой, по сравнению с лицами с гомозиготным генотипом CYP2C9*1/*1 [24]. Носители этих ОНП являются «медленными метаболизаторами» [25].…”