Significance of MDR1 gene polymorphism C3435T in predicting drug response in epilepsy

Shaheen, Uzma; Prasad, D Krishna; Sharma, Vandana; Turaga, Suryaprabha; Ahuja, Y.R.; Jyothy, A.; Munshi, Anjana

doi:10.1016/j.eplepsyres.2013.11.009

Cited by 43 publications

(22 citation statements)

References 27 publications

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“…In the present study, we showed that patients with epilepsy with the CC genotype of ABCB1 rs1045642 had a higher OXC concentration in comparison with CT and TT genotypes, suggesting patients with homozygous wild-type carriers required lower OXC maintenance dose to achieve the referenced effective plasma level. This was consistent with a previous study [6], which demonstrated that ABCB1 rs1045642 CC was associated with increased plasma CBZ levels. However, Wang et al's study has only indicated that ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were significantly associated with MHD and MHD + OXC plasma concentration in the group on OXC + Valproic acid (VPA) polytherapy, but no associations were observed between ABCB1 rs1045642 and plasma OXC concentration in patients with epilepsy receiving OXC monotherapy [11], which was inconsistent with our study.…”

Section: Discussionsupporting

confidence: 93%

“…Both proteins and mRNAs are overexpressed in the brain of patients with drug-resistant epilepsy [3][4][5]. Researches have found that ABCB1 and ABCC2 genetic polymorphisms were connected with the high incidence of drugresistant epilepsy, probably as the polymorphisms may affect the efflux activity of transporters in the endothelial cells of the bloodbrain barrier, decrease the concentrations of AEDs, and then contribute to the failure of AEDs [6,7]. Several studies have indicated ABCB1 and ABCC2 polymorphisms may be associated with the carbamazepine (CBZ) concentration and responsiveness [8,9].…”

Section: Introductionmentioning

confidence: 99%

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

Shen

Zhang

Liu

et al. 2017

Seizure

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Shen

Zhang

Liu

et al. 2017

Seizure

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“…Similarly many anticonvulsant drugs such as phenytoin, phenobarbital and clobazam are also ABC transporter substrates and subject to poor brain uptake (Nakanishi et al, 2013;Zhang et al, 2012). Moreover, single nucleotide polymorphisms (SNPs) in MDR1 increase the risk of resistance or greater interindividual response to antiepileptic and antipsychotic drugs (Bozina et al, 2008;Li et al, 2014;Shaheen et al, 2014;Vijayan et al, 2012). Our data support that CBD may be free from the complication of reduced brain uptake or varied interindividual response to drug therapy, at least that is mediated by the ABC transporters P-gp and Bcrp.…”

Section: Discussionsupporting

confidence: 54%

Peer Review #1 of "ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice (v0.1)"

Kang¹

2016

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Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various current antipsychotics and anticonvulsants. It is therefore important to assess whether CBD may be prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout (Abcb1a/b-/-), Bcrp knockout (Abcg2-/-), combined P-gp/Bcrp knockout (Abcb1a/b-/-Abcg2-/-) and WT mice were injected with CBD, before brain and plasma samples were collected and determined at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.

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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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Significance of MDR1 gene polymorphism C3435T in predicting drug response in epilepsy

Cited by 43 publications

References 27 publications

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

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

Peer Review #1 of "ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice (v0.1)"

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

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