Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Ponnala, Shivani; Chaudhari, Jaideep Ray; Jaleel, Momin Abdul; Bhiladvala, Dilnawaz; Kaipa, Prabhakar Rao; Das, Undurti N.; Hasan, Qurratulain

doi:10.1089/gtmb.2011.0225

Cited by 33 publications

(33 citation statements)

References 37 publications

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“…A lower response rate in carriers of the 2677TT genotype was reported [192], whereas 3435TT had no significant effect [193]. For phenytoin, 3435CC seems to confer a lower C 0 [194] and an increased resistance rate [195]. For valproic acid, the available studies did not find a significant effect on kinetics [196] or the response rate [197].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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Section: Antiepileptic Drugsmentioning

confidence: 99%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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“…However subsequent studies had provided conflicting results and failed to prove the original findings [14,15,16,17]. Moreover, other studies on different ethnic populations reported the opposite with 3435T homozygosity was the accused of resistance [18,19,20]. Sayyah and colleagues found in their study on idiopathic Iranian epileptic patients that there were more patients with CT and TT genotypes among those with lower number of seizures, and more patients with CC genotype among those with higher number of seizures [21].…”

Section: Discussionmentioning

confidence: 99%

The Association between Adenosine Triphosphate Binding Cassette B1 Cytosine 3435 Thymine Polymorphism and Pharmacoresistant Idiopathic Epilepsy: An Egyptian Study

Altaweel¹,

Kamel²,

Amin³

et al. 2019

IJCEN

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Background: P-glycoprotein (P-gp) is a drug efflux transporter present in the blood brain barrier whose function was suggested to be modified by a genetic polymorphism affecting ABCB1 C3435T gene at exon 26. Overexpression was related to homozygous C allele in some studies, however other studies in different ethnic populations showed relation to homozygous T allele, furthermore others failed to confirm any relation to resistance to therapeutic effects of AEDs. Aim of the study: Our aim is to find out the association between C3435T polymorphism and pharmacoresistance in idiopathic epilepsy in order to identify early the pharmacoresistant patients so we can select the proper AED and other proper therapeutic modalities. Patients and methods: Our case-control study was conducted on 44 idiopathic epileptic patients (22 drug-resistant and 22 drug-responsive epilepsy) and 44 healthy controls of comparable age and sex. Blood samples were obtained. Allele and genotype frequencies were evaluated between our study groups and their association with pharmacoresistance, some historical and semiology of epilepsy. Results: Our work revealed a lower risk of drug resistance in patients with the genotype CT (OR: 0.8) in comparison to genotypes CC and TT (OR: 1.2, 1 respectively) but the results were not statistically significant. However, significant association regarding daytime seizures was found with genotype CC in comparison to genotypes CT and TT. Conclusion: Daytime seizures were found to be more prevalent among those with CC genotype and this association was significant. The risk of drug resistant epilepsy was lower in patients with CT than those with CC and TT genotypes, but this association was not statistically significant in our study.

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“…For example, a meta-analysis suggested a correlation between rs1045642 and tacrolimus pharmacokinetics (Li et al, 2012). Other studies connect this SNP with therapeutic outcomes in gastric, lung, blood, and other cancers Yan et al, 2011) and responses to anti-epileptic (Ponnala et al, 2012) and rheumatoid arthritis drugs (Chen et al, 2011). Moreover, rs1045642 is associated with the risk of breast, renal, blood, and other cancers (Mhaidat et al, 2011;Qian et al, 2012;Wang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…For example, among Caucasians, the C3435T polymorphism in exon 26 correlates with expression of P-gp in the intestine, and people who are homozygous for the T allele show more than 2-fold lower duodenal P-gp protein expression levels compared with C homozygotes. Since concentrations of P-gp in the intestine determine the extent of drug absorption, genotype-related differences in bioavailability are seen for several drugs (e.g., digoxin) (Chen et al, 2011;Li et al, 2011;Yan et al, 2011;Ponnala et al, 2012). Substantial differences in allele frequencies have been reported in different racial groups.…”

Section: Introductionmentioning

confidence: 99%

Frequency of MDR1 single nucleotide polymorphisms in a Jordanian population, including a novel variant

Khabour

Alzoubi²,

Si³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. The multidrug resistance gene (MDR1 or ABCB1) codes for P-glycoprotein, which plays an important role in regulating absorption, distribution, and elimination of drugs. We examined MDR1 gene variants in 100 unrelated subjects from various regions of Jordan. The MDR1 gene was scanned using direct sequencing. Six rare variants in MDR1 were detected, including a new variant, T3075A. This variant did not affect the protein sequence (synonym for threonine). Among the common SNPs, the frequencies of rs1128503 (C1236T) genotypes were: 0.23 (CC), 0.41 (CT) and 0.36 (TT). For the rs2032582 (G2677T) SNP, genotype frequencies were 0.38 for GG, 0.45 for GT, 0.13 for TT, 0.03 for GA, and 0.01 for TA, whereas for rs1045642 (C3435T), genotype frequencies were 0.17 for CC, 0.5 for CT and 0.33 for TT. The observed distribution of the common variants in the Jordanian population was within the range detected in other populations. These data on MDR1 gene variants in the Jordanian population will be useful for investigations on response to P-glycoprotein substrate drugs.

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Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Cited by 33 publications

References 37 publications

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

The Association between Adenosine Triphosphate Binding Cassette B1 Cytosine 3435 Thymine Polymorphism and Pharmacoresistant Idiopathic Epilepsy: An Egyptian Study

Frequency of MDR1 single nucleotide polymorphisms in a Jordanian population, including a novel variant

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