[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients
Background P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [ 11 C]metoclopramide is a P-gp substrate for positron emission t...
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| Vydáno v: | Fluids and barriers of the CNS Ročník 21; číslo 1; s. 87 - 12 |
|---|---|
| Hlavní autoři: | , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
BioMed Central
28.10.2024
BioMed Central Ltd Springer Nature B.V BMC |
| Témata: | |
| ISSN: | 2045-8118, 2045-8118 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | Background
P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [
11
C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [
11
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.
Methods
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 [
11
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 (
K
1
) and from brain to plasma (
k
2
), and the total volume of distribution (
V
T
=
K
1
/
k
2
).
Results
DRE patients but not DSE patients showed significantly higher
k
2
values and a trend towards lower
V
T
values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (
k
2
: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).
Conclusions
[
11
C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant
k
2
seems to be the most sensitive parameter to measure increased P-gp function with [
11
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. [
11
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.
Trial registration
EudraCT 2019-003137-42. Registered 28 February 2020. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 PMCID: PMC11514750 |
| ISSN: | 2045-8118 2045-8118 |
| DOI: | 10.1186/s12987-024-00588-8 |