Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein
| العنوان: | Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein |
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| المؤلفون: | Hiroki Morishita, Kozue Okawa, Kentaro Yano, Kenta Mizoi, Takuo Ogihara, Misaki Ishii, Hiroshi Arakawa, Masaaki Ito |
| المصدر: | PLoS ONE PLoS ONE, Vol 15, Iss 10, p e0232438 (2020) |
| بيانات النشر: | Public Library of Science, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Side effect, Swine, Science, Aripiprazole, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Pimozide, Sertraline, medicine, Animals, Humans, Drug Interactions, ATP Binding Cassette Transporter, Subfamily B, Member 1, P-glycoprotein, Gastrointestinal tract, Multidisciplinary, biology, Chemistry, Biological Transport, Gastrointestinal Absorption, biology.protein, Medicine, LLC-PK1 Cells, Efflux, Caco-2 Cells, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug, Research Article |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23d5183a21cdd62f59f9796a2915ca8eTest http://europepmc.org/articles/PMC7595425Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....23d5183a21cdd62f59f9796a2915ca8e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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