Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy

Abstract

The results demonstrated the important role of the CYP 3A4*1B allelic variant as risk factor for developing drug resistance and CYP2D6, CYP2C19 SNPs and haplotypes may affect the response to antiepileptic drugs.

Functional Characterization of 22 CYP3A4 Protein Variants to Metabolize Ibrutinib In Vitro

“…It is clear that CYP3A4 plays a very important role in drug metabolism and exhibits significant variation in enzyme activity. More and more evidence indicates that CYP3A4 genetic polymorphisms could change the pharmacokinetics of its substrate drugs in clinic, which may result in side effects or therapeutic failures . Therefore, it is of great importance to functionally characterize the enzymatic activities of CYP3A4 variants in the metabolism of clinic drugs in vitro .…”

“…The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2,.5,.14,.15,.16,.28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22 CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib and also offer a reference to the personalized treatment of ibrutinib in clinic.…”

A Systems Biology Approach for Personalized Medicine in Refractory Epilepsy

“…A prevalent role in treatment failure or toxic effects of various pharmaceutical compounds can be ascribed to the variability in drug metabolism [48]. In approximately 90% of all administered drugs, biochemical pathway reactions are catalyzed by various cytochrome P450 enzymes (CYPs) [49,50,51]. So far, 57 genes encoding CYP enzymes have been cloned in the human genome and classified into different families (CYP1, CYP2, CYP3) and subfamilies (CYP1A, CYP2C), and further distinguished in several isoforms (CYP2C19, CYP2D6, CYP3A4) [52].…”

“…These polymorphisms have been studied in large populations, showing a great heterogeneity in the frequency of different alleles/genotypes. For example, the CYP3A4*1B and CYP2C9*3 allelic variants, and CYP2C9*3/*3 genotype are responsible of multiple drug-resistant phenotypes against antiepileptic drugs [49,53]. For additional details, the reader is referred to other studies [54,55,56].…”

<p>Genetic polymorphisms of CYP3A5, CHRM2, and ZNF498 and their association with epilepsy susceptibility: a pharmacogenetic and case–control study</p>

“…Epilepsy is a chronic neurological disorder with a prevalence of 0.6-1.0% and an incidence of 50-120/100.000 individuals per year. [1][2][3][4] Epilepsy characterized by uncontrolled electrical activity produced by a group of neurons. 5,6 It can be caused by different etiologies such as metabolic disorders and structural brain abnormalities in addition to idiopathic epilepsies which are caused mostly by genetic factors.…”