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

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Abstract

Genetic polymorphisms are related to the concentration and efficacy of oxcarbazepine (OXC). 10-Hydroxycarbazepine (MHD) is the major pharmacologically active metabolite of OXC, and it exerts an antiepileptic effect. This study aimed to explore the connection between the MHD concentration and genes such as ATP-binding cassette B1 (ABCB1), ATP-binding cassette C2 (ABCC2), UDP-glucuronosyltransferase-2B7 and sodium voltage-gated channel alpha subunit 2 (SCN2A), which participate in the antiepileptic function of OXC.

Total 218 Chinese epileptic patients, were stratified into different groups according to their age, body mass index (BMI) and OXC efficacy. The genotypes of 7 single nucleotide polymorphisms in all subjects were determined by polymerase chain reaction-improved multiple ligase detection reaction assay. The MHD plasma concentration was detected by high-performance liquid chromatography and then standardized through dosage and body weight.

In general, the ABCC2 rs2273697 mutant ( P = .026) required a significantly higher standardized MHD concentration. For age groups, carriers of the ABCC2 rs2273697 mutant showed a significantly higher standardized MHD concentration than noncarriers in the juvenile group ( P = .033). In terms of BMI, a significantly higher standardized MHD concentration was found in the ABCB1 rs2032582 mutant of the normal weight group ( P = .026). The SCN2A rs17183814 mutant required a significantly higher OXC maintenance ( P = .014) in the low-weight group, while lower OXC maintenance dose ( P = .044) and higher standardized MHD concentration ( P = .007) in the overweight group.

The ABCC2 rs2273697 polymorphism was significantly associated with MHD plasma concentration in the whole patient cohort and in patients stratified by different ages, this finding provides potential theoretical guidance for the rational and safe clinical use of OXC.

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Most cited references 36

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Optimal cut-off values of BMI, waist circumference and waist:height ratio for defining obesity in Chinese adults.

Dong-Qiang Zeng, Liu-yuan He, Shengyong Dong … (2014)

It has not been established which specific measures of obesity might be most appropriate for predicting CVD risk in Asians. The objectives of the present study were to determine the associations of BMI, waist circumference (WC) and waist:height ratio (WHtR) with CVD risk factors and to evaluate the optimal cut-off values to define overweight or obesity in Chinese adults. Data collected from seven nationwide health examination centres during 2008 and 2009 were analysed. The BMI, WC and WHtR of 244 266 Chinese adults aged ≥ 20 years included in the study were measured. Logistic regression models were fit to evaluate the OR of each CVD risk factor according to various anthropometric indices. Receiver operating characteristic (ROC) analyses were conducted to assess the optimal cut-off values to predict the risk of diabetes, hypertension, dyslipidaemia and the metabolic syndrome. WHtR had the largest areas under the ROC curve for all CVD risk factors in both sexes, followed by WC and BMI. The optimal cut-off values were approximately 24·0 and 23·0 kg/m2 for BMI, 85·0 and 75·0 cm for WC, and 0·50 and 0·48 for WHtR for men and women, respectively. According to well-established cut-off values, BMI was found to be a more sensitive indicator of hypertension in both men and women, while WC and WHtR were found to be better indicators of diabetes and dyslipidaemia. A combination of BMI and central obesity measures was found to be associated with greater OR of CVD risk factors than either of them alone in both sexes. The present study demonstrated that WHtR and WC may be better indicators of CVD risk factors for Chinese people than BMI.

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ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients.

Jian Qu, Bo-Ting Zhou, Ji-Ye Yin … (2012)

Some study found that ATP-binding cassette (ABC) efflux transporters play an important role in antiepileptic drug resistance, especially ABCB1 and ABCC2. The aims of this study were to evaluate the relationship between the genetic polymorphisms of ABCC2 and ABCB1 and the therapeutic efficacy of antiepileptic drugs (AEDs) in Chinese epileptic patients. ABCB1 rs1045642 (3435C>T) and ABCC2 rs717620 (-24C>T), rs3740066 (3972C>T), and rs2273697 (1249G>A) polymorphisms loci in 537 Chinese epilepsy patients (217 drug resistant patients and 320 drug responders) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). ABCC2 rs717620 -24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79-9.20], P= 0.001). The OR values of ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08-2.29], P= 0.018; OR = 1.49 [1.02-2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D'= 0.694) and rs3740066 (D'= 0.699). The frequencies of haplotypes TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance; ABCC2 1249G>A and ABCB1 3435C>T polymorphisms are not associated with AED resistance in our study. These data suggest that ABCC2 polymorphisms and haplotype may affect the response of antiepileptic drugs. © 2012 Blackwell Publishing Ltd.

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Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy.

J Cloyd, Yogita Ghodke-Puranik, Jeanette Birnbaum … (2012)

The aim of this study was to evaluate the association of genetic variants in the major genes involved in carbamazepine (CBZ) metabolism and transport with its pharmacokinetics in epilepsy patients. Twenty-five SNPs within seven CBZ pathway genes, namely CYP3A4, CYP3A5, EPHX1, NR1I2, UGT2B7, ABCB1 and ABCC2, were analyzed for association with CBZ pharmacokinetics in 90 epilepsy patients. The CYP3A4*1B SNP was significantly associated with CBZ clearance. Significant association of EPHX1 SNPs was observed with greater carbamazepine-10,11-trans dihydrodiol:carbamazepine 10-11 epoxide ratios. Among drug transporters, ABCB1 and ABCC2 SNPs were significantly associated with altered CBZ clearance. SNPs within CBZ pathway genes contribute to interpatient variation in CBZ pharmacokinetics and might contribute to pharmacoresistant epilepsy. Although our results need further clinical validation in a larger patient cohort, they indicate that genetic variation in CBZ pathway genes could influence its pharmacokinetics, and hence would have clinical significance.

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Author and article information

Journal

Journal ID (nlm-ta): Medicine (Baltimore)

Journal ID (iso-abbrev): Medicine (Baltimore)

Journal ID (publisher-id): MEDI

Title: Medicine

Publisher: Wolters Kluwer Health

ISSN (Print): 0025-7974

ISSN (Electronic): 1536-5964

Publication date Collection: March 2019

Publication date (Electronic): 22 March 2019

Volume: 98

Issue: 12

Electronic Location Identifier: e14908

Affiliations

[a ]Department of Pharmacy

[b ]Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders

[c ]Department of Pathology, Xiangya Hospital, Central South University, China.

Author notes

[∗ ]Correspondence: Zhicheng Gong, Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Hunan, China (e-mail: gongzhicheng@ 123456csu.edu.cn ); Zhijie Xu, Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Hunan, China (e-mail: xzj1322007@ 123456csu.edu.cn ).

Article

Publisher ID: MD-D-18-07388 Accession ID: 14908

DOI: 10.1097/MD.0000000000014908

PMC ID: 6708905

PubMed ID: 30896644

SO-VID: 10cf9962-37f7-4f9e-a299-850914544cbe

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This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

History

Date received : 13 October 2018

Date revision received : 30 January 2019

Date accepted : 21 February 2019

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Keywords: 10-hydroxycarbazepine,abcb1,abcc2,epilepsy,gene polymorphisms,oxcarbazepine,scn2a,ugt2b7

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Keywords: 10-hydroxycarbazepine, abcb1, abcc2, epilepsy, gene polymorphisms, oxcarbazepine, scn2a, ugt2b7

Comparison of oxcarbazepine efficacy and MHD concentrations relative to age and BMI : Associations among ABCB1, ABCC2, UGT2B7, and SCN2A polymorphisms

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Most cited references 36

Optimal cut-off values of BMI, waist circumference and waist:height ratio for defining obesity in Chinese adults.

ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients.

Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy.

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