Analysis of pimozide hERG inhibition by complex drug interactions via P-glycoprotein.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20729
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Takasaki University of Health and Welfare
• Principal Investigator: Liyanage Perera Manosika Buddhini 高崎健康福祉大学, 薬学部, 博士研究員 (50912606)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: ピモジド / ｐ-糖タンパク質 / 心筋細胞 / hERG / QT延長 / 薬物相互作用

Outline of Final Research Achievements

Pimozide, an antipsychotic drug, is an inhibitor of the hERG channel. A death has been reported in a boy who received pimozide together with sertraline and aripiprazole. In this study, we investigated the relationships between transporter-mediated intracellular accumulation and the hERG inhibitory effect of pimozide. The accumulation of pimozide in cardiomyocyte-derived AC16 cells was increased by sertraline and aripiprazole, which are thought to have a P glycoprotein (P-gp) inhibitory effect, and under siRNA conditions. These results　suggest P-gp inhibition increases pimozide accumulation in AC16 cells. We investigated the concentration-dependent hERG inhibitory effect of pimozide from　within AC16 cells. Addition of pimozide inhibited the hERG current with concentration dependence. This indicate P-gp-mediated interactions increases pimozide accumulation in AC16 cells, and the elevated pimozide levels within the cells may result in an　increased risk of hERG channel inhibition.

Free Research Field

drug-drug interactions

Academic Significance and Societal Importance of the Research Achievements

本研究の成果として、P-gpを介した相互作用によって心筋細胞内へのピモジドの蓄積量が増加することで、hERG阻害作用が増強される可能性が示唆された。ピモジドに限らずhERG阻害薬を有する薬物においては、同様のメカニズムによってQT延長や致死的不整脈発症の原因のひとつになる可能性が考えられた。薬物動態学的相互作用を検討する際には、血中濃度上昇を伴うsystemicなDDIのみならず、組織分布過程におけるトランスポーターを介したLocal-DDIについても考慮する必要性があるものと考えられた。今回の我々の研究成果は今後の医薬品開発や患者の医療安全に貢献できるものと思われる。