論文 - 詳細
| RRC ID | 27188 |
|---|---|
| 著者 | Hung CC, Chiou MH, Teng YN, Hsieh YW, Huang CL, Lane HY. |
| タイトル | Functional impact of ABCB1 variants on interactions between P-glycoprotein and methadone. |
| ジャーナル | PLoS One |
| Abstract |
Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp's interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates. |
| 巻・号 | 8(3) |
| ページ | e59419 |
| 公開日 | 2013-1-1 |
| DOI | 10.1371/journal.pone.0059419 |
| PII | PONE-D-12-39123 |
| PMID | 23527191 |
| PMC | PMC3602015 |
| 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* Analysis of Variance Blotting, Western Fluoresceins / metabolism Genetic Variation* HEK293 Cells Humans Immunoblotting Inhibitory Concentration 50 Kinetics Methadone / metabolism* Mutagenesis, Site-Directed Real-Time Polymerase Chain Reaction Rhodamine 123 / metabolism Verapamil |
| IF | 2.74 |
| 引用数 | 24 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Google+ |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | Human MDR1 cDNA (RDB01372) |