Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [18F]MC225 and PET

Varela, Lara García; Mossel, Pascalle; Aguiar, Pablo; Vazquez-Matias, Daniel A.; Waarde, Aren van; Willemsen, Antoon T. M.; Bartels, Anna L.; Colabufo, Nicola Antonio; Dierckx, Rudi; Elsinga, Philip H.; Luurtsema, Gert

doi:10.1016/j.jconrel.2022.05.026

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…The experimental protocol was approved by a local ethics committee for animal use (CETEA) and by the French ministry of agriculture (APAFIS#746620161104 17049220 v2). The sample size for each group was based on previous studies with the aim to compare the brain distribution of another P-gp PET probe [27].…”

Section: Animalsmentioning

confidence: 99%

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

et al. 2022

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[11C]metoclopramide PET imaging provides a sensitive and translational tool to explore P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Patients with neurological diseases are often treated with cytochrome (CYP) modulators which may impact the plasma and brain kinetics of [11C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [11C]metoclopramide was investigated in rats. Data obtained in a control group were compared with groups that were either orally pretreated with carbamazepine (45 mg/kg twice a day for 7 days before PET) or ritonavir (20 mg/kg, 3 h before PET) (n = 4 per condition). Kinetic modelling was performed to estimate the brain penetration (VT) of [11C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [11C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor VT of [11C]metoclopramide (p > 0.05). However, ritonavir significantly increased VT (p < 0.001), apparently behaving as an inhibitor of P-gp at the BBB. Our data suggest that treatment with potent CYP inducers such as carbamazepine does not bias the estimation of P-gp function at the BBB with [11C]metoclopramide PET. This supports further use of [11C]metoclopramide for studies in animals and patients treated with CYP inducers.

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Section: Animalsmentioning

confidence: 99%

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

et al. 2022

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“…[ 18 F]MPPF or [ 18 F]MC225). 26,27 However, this protocol is limited by the lack of availability of tariquidar for clinical use and the safety risk associated with the administration of a P-gp inhibitor in patients who receive concomitant medication. A further drawback of "avid" P-gp substrate radiotracers is their negligible baseline brain uptake which hinders the detection of an induction of P-gp function at the BBB.…”

Section: Introductionmentioning

confidence: 99%

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Mairinger,

Leterrier,

Filip

et al. 2023

J Cereb Blood Flow Metab

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The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [11C]metoclopramide to measure decreased cerebral P-gp function, we performed [11C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b(+/−) and homozygous Abcb1a/b(−/−) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [11C]metoclopramide was expressed as the area under the brain time-activity curve (AUCbrain) and compared with data previously obtained with ( R)-[11C]verapamil and [11C] N-desmethyl-loperamide. Abcb1a/b(+/−) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b(−/−) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b(−/−) from wild-type mice (2.5- to 4.6-fold increased AUCbrain, p ≤ 0.0001). However, only [11C]metoclopramide could discriminate Abcb1a/b(+/−) from wild-type mice (1.46-fold increased AUCbrain, p ≤ 0.001). After partial P-gp inhibition, differences in [11C]metoclopramide AUCbrain between Abcb1a/b(+/−) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [11C]metoclopramide AUCbrain and ex-vivo-measured P-gp immunofluorescence (r = −0.9875, p ≤ 0.0001). Our data suggest that [11C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor.

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“…Efforts have been made to develop dedicated PET probes to investigate the impact of efflux transporters of the ATP-binding cassette (ABC) family on drug delivery to selected organs such as the brain [15,16] or the lungs [17]. The role of SLC transporters did not receive as much attention although their importance for WBPK remains unclear [2,18].…”

Section: Introductionmentioning

confidence: 99%

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

Marie

Breuil

Chalampalakis

et al. 2022

Biomedicine & Pharmacotherapy

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Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [18F]MC225 and PET

Cited by 7 publications

References 38 publications

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

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Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [18F]MC225 and PET

Cited by 7 publications

References 38 publications

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

[11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

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[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier