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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| Principais autores: | , , , , , , , , , |
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| Formato: | Livro |
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MDPI AG,
2022-08-01T00:00:00Z.
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| Resumo: | 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. |
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| Descrição do item: | 10.3390/pharmaceutics14081658 1999-4923 |