Reference - Detail
| 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 | 2008-5-1 |
| 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 | 2.94 |
| Times Cited | 42 |
| WOS Category | PHARMACOLOGY & PHARMACY BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY |
| Resource | |
| DNA material | Human MDR1 cDNA (RDB01372) |