Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Export

@article{citeulike:5779164, abstract = {OBJECTIVE: The ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs). METHODS AND RESULTS: Transport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose-response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs. CONCLUSION: Our findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses.}, author = {Hung, Chin-Chuan C. and Chen, Chih-Chuan C. and Lin, Chun-Jung J. and Liou, Horng-Huei H.}, citeulike-article-id = {5779164}, citeulike-linkout-0 = {http://dx.doi.org/10.1097/FPC.0b013e3282f85e36}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18408562}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18408562}, doi = {10.1097/FPC.0b013e3282f85e36}, issn = {1744-6872}, journal = {Pharmacogenetics and genomics}, keywords = {epilepsy, genetics, mdr1, pharmacogenetics, phenotype}, month = {May}, number = {5}, pages = {390--402}, posted-at = {2009-09-13 15:25:48}, priority = {2}, title = {Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs.}, url = {http://dx.doi.org/10.1097/FPC.0b013e3282f85e36}, volume = {18}, year = {2008} }

TY - JOUR ID - citeulike:5779164 L3 - citeulike-article-id:5779164 N2 - OBJECTIVE: The ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs). METHODS AND RESULTS: Transport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose-response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs. CONCLUSION: Our findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses. IS - 5 JF - Pharmacogenetics and genomics SN - 1744-6872 EP - 402 TI - Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. VL - 18 SP - 390 KW - epilepsy KW - genetics KW - mdr1 KW - pharmacogenetics KW - phenotype AU - Hung, Chin-Chuan AU - Chen, Chih-Chuan AU - Lin, Chun-Jung AU - Liou, Horng-Huei PY - 2008/05// UR - http://dx.doi.org/10.1097/FPC.0b013e3282f85e36 ER -