RRC ID 3807
Author Hung CC, Chen CC, Lin CJ, Liou HH.
Title Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs.
Journal Pharmacogenet. Genomics
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.
Volume 18(5)
Pages 390-402
Published 2008-5
DOI 10.1097/FPC.0b013e3282f85e36
PII 01213011-200805000-00003
PMID 18408562
MeSH ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics* ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology Anticonvulsants / pharmacology Anticonvulsants / therapeutic use* Base Sequence Cells, Cultured Dose-Response Relationship, Drug Drug Resistance / genetics Epilepsy / diagnosis Epilepsy / drug therapy* Epilepsy / genetics* Fluoresceins / pharmacokinetics Fluorescent Dyes / pharmacokinetics Humans Polymorphism, Single Nucleotide / physiology* Prognosis Rhodamine 123 / pharmacokinetics
IF 2.184
Times Cited 38
WOS Category PHARMACOLOGY & PHARMACY BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY
Resource
DNA material Human MDR1 cDNA (RDB01372)