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The inhibition of human ether‐a‐go‐go‐related gene (hERG) channels is a known cause of QT prolongation triggered by antipsychotic drugs. Our previous studies suggest that P‐glycoprotein (P‐gp)‐mediated drug interactions may lead to increased gastrointestinal absorption of pimozide and its accumulation in cardiomyocytes, thereby enhancing the inhibitory effect of hERG channels. There is a paucity of epidemiological studies examining the risk of QT prolongation by antipsychotic drugs in terms of P‐gp‐mediated interactions with concomitant drugs. Therefore, using the Japanese Adverse Event Reporting Database, we investigated whether the risk of QT prolongation triggered by antipsychotic drugs associated with hERG inhibition is affected by the concomitant use of selective serotonin reuptake inhibitors (SSRIs) associated with P‐gp inhibition. The results showed that the frequency of QT prolongation increased when the antipsychotic drugs quetiapine and sulpiride, which are P‐gp substrates, were combined with SSRIs with P‐gp inhibition. In contrast, no association with QT prolongation was observed in patients on non‐P‐gp‐substrate antipsychotics, irrespective of the P‐gp inhibitory effect of the concomitant SSRI. These results suggest that P‐gp‐mediated interactions are a risk factor for antipsychotic‐induced QT prolongation. There is a need for further investigation into the risks of specific drug combinations. [ABSTRACT FROM AUTHOR]

Lung cancer metastasis often leads to a poor prognosis for patients. Mesenchymal-epithelial transition (MET) is one key process associated with metastasis. MET has also been linked to multidrug drug resistance (MDR). MDR arises from the overactivity of drug efflux transporters such as P-glycoprotein (P-gp) which operate at the cell plasma membrane, under the regulatory control of the scaffold proteins ezrin (Ezr), radixin (Rdx), and moesin (Msn), collectively known as ERM proteins. The current study was intended to clarify the functional changing of P-gp and the underlying mechanisms in the context of dexamethasone (DEX)-induced MET in lung cancer cells. We found that the mRNA and membrane protein expression of Ezr and P-gp was increased in response to DEX treatment. Moreover, the DEX-treated group exhibited an increase in Rho123 efflux, and it was reversed by treatment with the P-gp inhibitor verapamil or Ezr siRNA. The decrease in cell viability with paclitaxel (PTX) treatment was mitigated by pretreatment with DEX. The increased expression and activation of P-gp during the progression of lung cancer MET was regulated by Ezr. The regulatory mechanism of P-gp expression and activity may differ depending on the cell status. [Display omitted] • EMT and MET are implicated in MDR in cancer, promoting drug efflux. • Ezr and MSN are known to be scaffold proteins for P-gp in lung cancer. • DEX-induced MET enhanced P-gp expression and activation by EZR in lung cancer. • The regulatory mechanism of P-gp expression may differ depending on the cell status. [ABSTRACT FROM AUTHOR]