P-Glycoprotein–Mediated Pharmacokinetic Interactions Increase Pimozide hERG Channel Inhibition

P‐Glycoprotein‐Mediated Interaction Is a Risk Factor for QT Prolongation in Concomitant Use of Antipsychotics and SSRIs as P‐Glycoprotein‐Mediated Inhibitors: Analysis of the Japanese Adverse Drug Event Report Database

“…Furthermore, patch-clamp studies showed that pimozide inhibited hERG channels from within the cells and enhanced hERG inhibition in a concentrationdependent manner in the cells. 9 In other words, the pharmacokinetic interaction via P-gp increased the blood concentration of pimozide (a systemic DDI), and intramyocardial cell concentrations (a local DDI) may enhance hERG channel inhibition and increase the risk of QT prolongation. This means that P-gp inhibition may lead to stronger cardiotoxicity in car-diotoxic P-gp substrate drugs associated with hERG channel inhibition.…”

“…The accumulation of pimozide in myocardial‐derived AC16 cells was increased by the combination of sertraline and aripiprazole. Furthermore, patch‐clamp studies showed that pimozide inhibited hERG channels from within the cells and enhanced hERG inhibition in a concentration‐dependent manner in the cells 9 . In other words, the pharmacokinetic interaction via P‐gp increased the blood concentration of pimozide (a systemic DDI), and intramyocardial cell concentrations (a local DDI) may enhance hERG channel inhibition and increase the risk of QT prolongation.…”

“…Thirteen antipsychotics with hERG channel inhibitory activity, [11][12][13][14][15][16][17][18][19][20][21][22] extracted from the JADER database, were classified according to whether or not they were substrates of P-gp or whether this was unknown: fluphenazine, olanzapine, paliperidone, pimozide, quetiapine, risperidone, and sulpiride were classified as the P-gp substrate group; chlorpromazine, clozapine, and haloperidol were classified as the non-P-gp substrate group 9,[23][24][25][26] ; and aripiprazole, prochlorperazine, and sultopride were excluded from the analysis for a lack of definitive data on whether or not they were P-gp substrates (Table S1). QT prolongation as an adverse drug reaction was defined as "Electrocardiogram (ECG) QT prolongation," "ECG QT interval abnormality," or "QT prolongation syndrome," reported as Preferred Terms based on the MedDRA 25.0 definition, 27 and furthermore "suspect drug" with suspected QT prolongation based on the reporter's classification, "concomitant drug", and all data on "concomitant medications" and "suspected interactions" were included.…”

“…Recently, P‐gp has been found to be expressed in cardiac muscle and may function as a defense mechanism against cardiotoxic substances. We have investigated the possibility that the combination of pimozide, a substrate drug of P‐gp, and sertraline, a P‐gp inhibitor, increases the gastrointestinal absorption and distribution of pimozide to the myocardium, and enhances the inhibitory effect on the hERG channel 8,9 . Antipsychotics and antidepressants are often used in combination clinically, 10 and it is possible that other antipsychotics may potentiate hERG inhibition by a similar mechanism.…”