Polymorphic Variants of SCN1A and EPHX1 Influence Plasma Carbamazepine Concentration, Metabolism and Pharmacoresistance in a Population of Kosovar Albanian Epileptic Patients

Daci, Armond; Beretta, Giangiacomo; Vllasaliu, Driton; Shala, Aida Loshaj; Govori, Valbona; Norata, Giuseppe Danilo; Krasniqi, Shaip

doi:10.1371/journal.pone.0142408

Cited by 46 publications

(32 citation statements)

References 73 publications

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“…We did not observe any genomewide significant associations with CBZ metabolic ratio ( Figure 3). 16 We did not replicate this finding (rs2234922; P = 0.303) but we observed a nominally significant association between an intronic EPHX1 SNP (c.365-2139T>C) and CBZ metabolic ratio (rs4653689; P = 1.1 × 10-4). Polymorphisms in CYP3A4 and EPHX1 have been shown to associate with interindividual variability of CBZ metabolism.…”

Section: Resultscontrasting

confidence: 56%

“…It had been reported that homozygous carriers of the EPHX1 c.416A>G SNP (rs2234922) seemingly show a reduced CBZ metabolism, as measured by a significantly decreased metabolic ratio. 16 We did not replicate this finding (rs2234922; P = 0.303) but we observed a nominally significant association between an intronic EPHX1 SNP (c.365-2139T>C) and CBZ metabolic ratio (rs4653689; P = 1.1 × 10-4).…”

Section: Resultscontrasting

confidence: 56%

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A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

et al. 2019

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Summary Objective To ascertain the clinical and genetic factors contributing to carbamazepine‐ and oxcarbazepine‐induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy. Methods We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ‐diol to unchanged drug precursor substrate as measured in serum. Results Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome‐wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome‐wide significant associations with CBZ metabolic ratio were found. Significance Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

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Section: Resultscontrasting

confidence: 56%

Section: Resultscontrasting

confidence: 56%

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

et al. 2019

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“…Furthermore, evidence of microsomal epoxide hydrolase activity at or near the blood-brain barrier has been reported (Ghersi-Egea et al, 1994). Carbamazepine, phenobarbital, and phenytoin are three xenobiotics with well characterized metabolic pathways involving epoxide hydrolase, with recent evidence suggesting that single nucleotide polymorphisms in the microsomal epoxide hydrolase gene EPHX1 influence carbamazepine exposure in vivo (El-Sherbeni and El-Kadi, 2014;Zhu et al, 2014;Daci et al, 2015).…”

Section: Epoxide Hydrolasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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“…Secondly, genetic differences in different races may be also an important factor. Thirdly, different treatments, mono-or combination AEDs, may also affect treatment results of AEDs [17,36,37]. A SNP-SNP interaction, rs7598931 and rs12233719 located in SCN2A and UGT2B7 separately, associated with VPA responses was first found.…”

Section: Biomed Research Internationalmentioning

confidence: 99%

Association of SCN1A, SCN2A, and UGT2B7 Polymorphisms with Responsiveness to Valproic Acid in the Treatment of Epilepsy

et al. 2020

BioMed Research International

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Purpose. The efficacy of valproic acid (VPA) varies widely in clinical treatment of epileptic patients. Our study is aimed at exploring a potential association between polymorphisms of SCN1A, SCN2A, and UGT2B7 genetic factors and VPA responses. Methods. In this observational study, a total of 114 epileptic patients only treated with VPA for at least 1 year were included to explore the genetic polymorphisms of drug responses (mean follow-up time: 3.68±1.78 years). Thirty-one single-nucleotide polymorphisms (SNPs) in three candidate genes that related with drug-metabolizing enzymes and receptors were genotyped. Results. Of the 31 SNPs, eight were significantly associated with VPA responses, including rs1381105, rs2162600, rs10197716, rs2119068, rs2119067, rs353116, rs353112 and rs6740895. The interaction between rs10197716 and rs2119068 was the most significantly correlated with VPA responses compared with other combinations (the highest VPA-responsive rate 0.92 versus the lowest VPA-responsive rate 0.33, p=0.007). Conclusion. The study indicated that eight SNPs and SNP-SNP interaction may be associated with VPA responses in Chinese Han epileptic patients. The SNPs were rs1381105 (SCN1A), rs2162600 (SCN1A), rs10197716 (SCN2A), rs2119068 (SCN2A), rs2119067 (SCN2A), rs353116 (SCN2A), rs353112 (SCN2A) and rs6740895 (SCN2A), respectively. The interaction between the three pairs of rs10197716-rs2119068, rs10197716-rs11889342 and rs7598931-rs12233719 was the most significant for VPA. This implied that these SNPs may play an important role in the pharmacogenomics mechanism of valproic acid.

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Polymorphic Variants of SCN1A and EPHX1 Influence Plasma Carbamazepine Concentration, Metabolism and Pharmacoresistance in a Population of Kosovar Albanian Epileptic Patients

Cited by 46 publications

References 73 publications

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Association of SCN1A, SCN2A, and UGT2B7 Polymorphisms with Responsiveness to Valproic Acid in the Treatment of Epilepsy

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