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The radiolabelled antiemetic drug [<jats:sup>11<\/jats:sup>C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [<jats:sup>11<\/jats:sup>C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [<jats:sup>11<\/jats:sup>C]metoclopramide on a fully-integrated PET\/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (<jats:italic>K<\/jats:italic><jats:sub>1<\/jats:sub>) and from brain to plasma (<jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub>), and the total volume of distribution (<jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub> = <jats:italic>K<\/jats:italic><jats:sub>1<\/jats:sub>\/<jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub>).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>DRE patients but not DSE patients showed significantly higher <jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub> values and a trend towards lower <jats:italic>V<\/jats:italic><jats:sub>T<\/jats:sub> values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (<jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub>: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>[<jats:sup>11<\/jats:sup>C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant <jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub> seems to be the most sensitive parameter to measure increased P-gp function with [<jats:sup>11<\/jats:sup>C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and\/or safety of drugs. [<jats:sup>11<\/jats:sup>C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>EudraCT 2019-003137-42. Registered 28 February 2020.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12987-024-00588-8","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T08:40:29Z","timestamp":1730104829000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients"],"prefix":"10.1186","volume":"21","author":[{"given":"Myriam El","family":"Biali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Breuil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Jackwerth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Severin","family":"Mairinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"W\u00f6lfl-Duchek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Bamminger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Rausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Nics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Hacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Rodrigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane","family":"Bouilleret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Zeitlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Pataraia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Tournier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"588_CR1","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1073\/pnas.86.2.695","volume":"86","author":"C Cordon-Cardo","year":"1989","unstructured":"Cordon-Cardo C, O\u2019Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al. 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