Dataset Information

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11C-Metoclopramide Assessed with PET Imaging in Humans.

ABSTRACT: PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate 11C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive 11C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution (V T) and the influx (K 1) and efflux (k 2) rate constants between plasma and selected brain regions. Furthermore, 11C-metoclopramide washout from the brain was estimated by determining the elimination slope (k E,brain) of the brain time-activity curves. Results: In baseline scans, 11C-metoclopramide showed appreciable brain distribution (V T = 2.11 ± 0.33 mL/cm3). During CsA infusion, whole-brain gray matter V T and K 1 were increased by 29% ± 17% and 9% ± 12%, respectively. K 2 was decreased by 15% ± 5%, consistent with a decrease in k E,brain (-32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.

SUBMITTER: Tournier N

PROVIDER: S-EPMC6604692 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate <sup>11</sup>C-Metoclopramide Assessed with PET Imaging in Humans.

Tournier Nicolas N Bauer Martin M Pichler Verena V Nics Lukas L Klebermass Eva-Maria EM Bamminger Karsten K Matzneller Peter P Weber Maria M Karch Rudolf R Caillé Fabien F Auvity Sylvain S Marie Solène S Jäger Walter W Wadsak Wolfgang W Hacker Marcus M Zeitlinger Markus M Langer Oliver O

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20190110 7

PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate <sup>11</sup>C-metoc ...[more]

PMID: 30630940

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Project description:P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic ?-amyloid (A?) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of A? deposits in the brain by enhancing clearance of A? peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a ?-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3?-ol-20-one-16?-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and A? levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (k E,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in k E,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in A? levels. There was a significant positive correlation between k E,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in k E,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11C-metoclopramide in all animal groups. Conclusion: 11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.

Dataset Information

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11C-Metoclopramide Assessed with PET Imaging in Humans.

Publications

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate <sup>11</sup>C-Metoclopramide Assessed with PET Imaging in Humans.

Similar Datasets

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