論文 - 詳細
| RRC ID | 63751 |
|---|---|
| 著者 | Morishita H, Okawa K, Ishii M, Mizoi K, Ito MA, Arakawa H, Yano K, Ogihara T. |
| タイトル | Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein. |
| ジャーナル | PLoS One |
| Abstract |
Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate (Jmax) and half-saturation concentration (Kt) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect. |
| 巻・号 | 15(10) |
| ページ | e0232438 |
| 公開日 | 2020-1-1 |
| DOI | 10.1371/journal.pone.0232438 |
| PII | PONE-D-20-10400 |
| PMID | 33119612 |
| PMC | PMC7595425 |
| MeSH | ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors* Animals Aripiprazole / pharmacology* Biological Transport Caco-2 Cells Drug Interactions Gastrointestinal Absorption Humans LLC-PK1 Cells Pimozide / pharmacokinetics* Sertraline / pharmacology* Swine |
| IF | 2.74 |
| 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 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 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 | |
| ヒト・動物細胞 | LLC-GA5-CoL150(RCB0871) |