Effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy

Shen, Chun‐Hong; Zhang, Bijun; Liu, Zhongfan; Tang, Ye-Lei; Zhang, Yinxi; Wang, Shan; Guo, Yi; Ding, Yao; Ding, Meiping

doi:10.1016/j.seizure.2017.07.015

Cited by 28 publications

(23 citation statements)

References 33 publications

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“…ABCB1 rs1045642 and UGT2B7 rs7439366 affect oxcarbazepine pharmacokinetics and pharmacodynamics in Han Chinese epileptic patients [296]. PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC influence the pharmacokinetics and pharmacodynamics of carbamazepine [297]. ABCB1 c.3435C>T, CYP3A4*1G, CYP3A5*3, POR*28, and EPHX1 c.416A>G and c.128G>C variants influence carbamazepine metabolism in Chinese patients [298].…”

Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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“…The median levels of total bilirubin and direct bilirubin of these patients were 91 and 50 µmol/l (normal reference for total bilirubin range was 3.4-17.1 µmol/l and the direct bilirubin range was 0-6.8 µmol/l), respectively. The clinical characteristics of the patients are shown in Table II (11) and p.V417I (c.1362G>A) (12)] were identified across the 7 patients, and the distribution of these variants is shown in Fig. 1A.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the missense variant p.V417I (c.1362G>A) in exon 10 harbored by the case no. 6 has previously been reported as a single-nucleotide polymorphism (SNP) (12). Further details on the variants identified in the ABCC2 gene are shown in Table III.…”

Section: Resultsmentioning

confidence: 99%

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Mutation analysis of the ABCC2 gene in Chinese patients with Dubin‑Johnson syndrome

Zhang

Jia

et al. 2018

Exp Ther Med

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Dubin-Johnson syndrome (DJS) is a rare, autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia, caused by a mutation in the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene coding the multidrug resistance-associated protein 2 (MRP2) protein. ABCC2 mutations have been identified in patients with DJS worldwide; however, the mutation pattern of ABCC2 in China is not well studied. In the present study, the mutation pattern of the ABCC2 gene in Chinese patients with DJS was investigated. A total of 7 clinically confirmed patients with DJS were enrolled, and mutation analysis of the ABCC2 gene was performed by Sanger sequencing of genomic DNA extracted from whole blood. All 32 exons and the adjacent splice junction areas were sequenced. All cases were identified to harbor at least one non-synonymous variant in the ABCC2 gene, including three known mutations in 3 cases and three novel variants (p.G693R, p.G808V and p.E647X) in the other 4 cases, with the known p.R393W and the novel p.G693R and p.E647X variants identified in 2 of the 7 cases (28.6%), respectively. All the identified mutations were heterozygous, and 1 case presented with a compound heterozygous mutation, namely p.G693R/p.G808V, while the other cases carried only one single mutation. The loss of membrane expression of MRP2 caused by the novel nonsense variant, p.E647X, was confirmed by immunohistochemical analysis of liver biopsy. The present study provided the first report on the mutation patterns of the ABCC2 gene in Chinese patients with DJS, and the clinical association of these mutations with the syndrome.

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“…Recent studies indicate that the main cause of OXC resistance is the genetic polymorphism existing in the genes encoding for proteins associated with OXC metabolizing enzymes, transporter proteins, or target proteins and receptors. [6] By checking the database (http://www.pharmgkb.org/do/) and literatures, we found 4 single nucleotide polymorphisms (SNPs) that were closely related to OXC, including ATP-binding cassette B1 (ABCB1) rs1045642, [7] ATP-binding cassette C2 (ABCC2) rs2273697, [8] ABCC2 rs717620, [9] and UDP-glucuronosyltransferase-2B7 (UGT2B7) rs7439366. [7] The ABCB1 rs1045642 mutant was found to be related to a higher normalized OXC concentration, [7] and meta-analyses have observed the close association between the ABCB1 rs1045642 polymorphism and drug resistance in Caucasian and Chinese patients.…”

Section: Introductionmentioning

confidence: 99%

Comparison of oxcarbazepine efficacy and MHD concentrations relative to age and BMI

et al. 2019

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Effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy

Abstract: These results suggested that ABCB1 rs1045642 and UGT2B7 rs7439366 may affect OXC pharmacokinetics and therapeutic efficacy in Han Chinese patients with epilepsy. However, further studies in larger populations and other ethnic groups are required.

Cited by 28 publications

References 33 publications

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Mutation analysis of the ABCC2 gene in Chinese patients with Dubin‑Johnson syndrome

Comparison of oxcarbazepine efficacy and MHD concentrations relative to age and BMI

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