Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients

Zhou, Yifei; Wang, Xueding; Li, Hongliang; Zhang, Jie; Chen, Ziyi; Xie, Wen; Zhang, Jinxin; Li, Jiali; Zhou, Liemin; Huang, Min

doi:10.1016/j.dmpk.2015.05.002

Cited by 40 publications

(24 citation statements)

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“…One in vitro study excluded lamotrigine as a potential ABCG2 transporter substrate [23], but a subsequent one identified it as a substrate for human ABCG2 at therapeutic concentrations [21]. Two studies in Chinese patients reported on the impact of ABCG2 polymorphisms on lamotrigine disposition variant allele carriage at ABCG2 421 C>A was associated with somewhat lower troughs vs. wild type genotype in one study [24], while in another one, variant allele homozygotes had higher lamotrigine concentrations than wild type homozygotes and heterozygotes [25]. In vitro, valproic acid was shown to concentration-dependently increase expression of ABCG2 in human trophoblast BeWo cell line [26], making it plausible to hypothesize about ABCG2 transporter as an additional potential site of lamotrigine-valproate interaction.…”

Section: Introductionmentioning

confidence: 99%

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Domjanović

Lovrić

Trkulja

et al. 2018

Brit J Clinical Pharma

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Section: Introductionmentioning

confidence: 99%

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Domjanović

Lovrić

Trkulja

et al. 2018

Brit J Clinical Pharma

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“…Through the two‐step selection process represented in Figure , seven studies were finally selected. Characteristics of the included studies are presented in Table . Two studies on UGT1A4 70C>A, five studies on UGT1A4 142T>G, two studies on UGT2B7 ‐161C>T and one study on UGT2B7 802C>T genetic polymorphisms were included.…”

Section: Resultsmentioning

confidence: 99%

“…This has led to many studies attempting to correlate changes in lamotrigine concentration with UGT genotype, and several studies suggest that UGT genetic polymorphisms strongly influence lamotrigine concentration . By contrast, other studies observed no significant differences in lamotrigine concentration according to UGT genotype …”

Section: Introductionmentioning

confidence: 99%

Meta‐analysis of the Influence of UGT Genetic Polymorphisms on Lamotrigine Concentration

Kim

2018

Basic Clin Pharma Tox

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Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are involved in the metabolism of lamotrigine, but whether the UGT1A4 and UGT2B7 genetic polymorphisms affect lamotrigine concentration remains controversial. Thus, the objective of this meta-analysis was to analyse the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration. Through searching, screening, selection, data extraction and quantitative analyses, the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration-to-dose ratio (CDR) was assessed by meta-analysis of nine studies. Neither UGT1A4 70C>A nor 142T>G significantly affected lamotrigine CDR values (standardized difference in means [SDM] = 0.433, 95% confidence interval [CI] = -0.380-1.302; SDM = -0.458, 95% CI = -1.141-0.224, respectively). Only the UGT2B7 -161C>T homozygous variant had significantly higher CDR values than the wild-type (WT) and heterozygous variant (SDM = 0.634, 95% CI = 0.056-1.222). In conclusion, CDR of lamotrigine was significantly higher for the UGT2B7 -161C>T homozygous variant than for the WT and heterozygous variant. Thus, UGT2B7 -161C>T homozygous variant needs to receive reduced dose.

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“…Polymorphisms of UGT2B7 affected the metabolism of AEDs such as VPA, CBZ and lamotrigine (LTG), and UGT2B7 was associated with oxcarbazepine (OXC) maintenance doses, which were useful for the personalization of OXC therapy [12,13]. Some studies on ABCB1, a drug transporter gene, indicated that genetic polymorphisms were associated with resistance of AEDs in patients with epilepsy [14,15]. SCN1A and SCN2A genes encoding the sodium channels were related to the efficacy, dose, and toxicity of multiple antiepileptic drugs [16].…”

Section: Introductionmentioning

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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Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients

Cited by 40 publications

References 47 publications

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Meta‐analysis of the Influence of UGT Genetic Polymorphisms on Lamotrigine Concentration

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

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