Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging
Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomograph...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/8/1658 |
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| author | Louise Breuil Sébastien Goutal Solène Marie Antonio Del Vecchio Davide Audisio Amélie Soyer Maud Goislard Wadad Saba Nicolas Tournier Fabien Caillé |
| author_facet | Louise Breuil Sébastien Goutal Solène Marie Antonio Del Vecchio Davide Audisio Amélie Soyer Maud Goislard Wadad Saba Nicolas Tournier Fabien Caillé |
| author_sort | Louise Breuil |
| collection | DOAJ |
| description | Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [<sup>11</sup>C]domperidone and [<sup>11</sup>C]metoclopramide. In P-gp-overexpressing cells, the IC<sub>50</sub> of tariquidar, a potent P-gp inhibitor, was drastically different using [<sup>11</sup>C]domperidone (221 nM [198–248 nM]) or [<sup>11</sup>C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [<sup>11</sup>C]domperidone compared with [<sup>11</sup>C]metoclopramide (<i>p</i> < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUC<sub>brain</sub>) of [<sup>11</sup>C]metoclopramide was 2.4-fold higher compared with [<sup>11</sup>C]domperidone (<i>p</i> < 0.001), consistent with a 1.8-fold higher BBB penetration (AUC<sub>brain</sub>/AUC<sub>plasma</sub>). The maximal increase in the brain exposure (2.9-fold, <i>p</i> < 0.0001) and BBB penetration (2.9-fold, <i>p</i> < 0.0001) of [<sup>11</sup>C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [<sup>11</sup>C]domperidone (<i>p</i> > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB. |
| first_indexed | 2024-03-09T09:50:51Z |
| format | Article |
| id | doaj.art-4e969819b45f42e6b09eeef63d0adaeb |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T09:50:51Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-4e969819b45f42e6b09eeef63d0adaeb2023-12-02T00:09:56ZengMDPI AGPharmaceutics1999-49232022-08-01148165810.3390/pharmaceutics14081658Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET ImagingLouise Breuil0Sébastien Goutal1Solène Marie2Antonio Del Vecchio3Davide Audisio4Amélie Soyer5Maud Goislard6Wadad Saba7Nicolas Tournier8Fabien Caillé9Laboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceCEA, Département Médicaments et Technologies pour la Santé, SCBM, Université Paris-Saclay, 91190 Gif-sur-Yvette, FranceCEA, Département Médicaments et Technologies pour la Santé, SCBM, Université Paris-Saclay, 91190 Gif-sur-Yvette, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceLaboratoire d’Imagerie Biomédicale Multimodale (BIOMAPS), Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, FranceDomperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [<sup>11</sup>C]domperidone and [<sup>11</sup>C]metoclopramide. In P-gp-overexpressing cells, the IC<sub>50</sub> of tariquidar, a potent P-gp inhibitor, was drastically different using [<sup>11</sup>C]domperidone (221 nM [198–248 nM]) or [<sup>11</sup>C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [<sup>11</sup>C]domperidone compared with [<sup>11</sup>C]metoclopramide (<i>p</i> < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUC<sub>brain</sub>) of [<sup>11</sup>C]metoclopramide was 2.4-fold higher compared with [<sup>11</sup>C]domperidone (<i>p</i> < 0.001), consistent with a 1.8-fold higher BBB penetration (AUC<sub>brain</sub>/AUC<sub>plasma</sub>). The maximal increase in the brain exposure (2.9-fold, <i>p</i> < 0.0001) and BBB penetration (2.9-fold, <i>p</i> < 0.0001) of [<sup>11</sup>C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [<sup>11</sup>C]domperidone (<i>p</i> > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB.https://www.mdpi.com/1999-4923/14/8/1658ATP-binding cassettedrug–drug interactionmembrane transporterneuropharmacologypharmacokineticsPET imaging |
| spellingShingle | Louise Breuil Sébastien Goutal Solène Marie Antonio Del Vecchio Davide Audisio Amélie Soyer Maud Goislard Wadad Saba Nicolas Tournier Fabien Caillé Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging Pharmaceutics ATP-binding cassette drug–drug interaction membrane transporter neuropharmacology pharmacokinetics PET imaging |
| title | Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging |
| title_full | Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging |
| title_fullStr | Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging |
| title_full_unstemmed | Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging |
| title_short | Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging |
| title_sort | comparison of the blood brain barrier transport and vulnerability to p glycoprotein mediated drug drug interaction of domperidone versus metoclopramide assessed using in vitro assay and pet imaging |
| topic | ATP-binding cassette drug–drug interaction membrane transporter neuropharmacology pharmacokinetics PET imaging |
| url | https://www.mdpi.com/1999-4923/14/8/1658 |
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