Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [C]Metoclopramide

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2021 Jan 22

PMID 33481175

Authors

Martin Bauer

Sandra Barna

Matthias Blaickner

Konstantin Prosenz

Karsten Bamminger

Verena Pichler

Nicolas Tournier

Marcus Hacker

Markus Zeitlinger

Georgios Karanikas

Oliver Langer

Affiliations

Soon will be listed here.

Abstract

Purpose: To assess in healthy volunteers the whole-body distribution and dosimetry of [C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.

Procedures: Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.

Results: The majority of the administered dose of [C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively.

Conclusions: [C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [C]metoclopramide was comparable to other C-labeled PET tracers.

References

Atkins H, Thomas S, Buddemeyer U, Chervu L . MIRD Dose Estimate Report No. 14: radiation absorbed dose from technetium-99m-labeled red blood cells. J Nucl Med. 1990; 31(3):378-80. View

Zoufal V, Mairinger S, Brackhan M, Krohn M, Filip T, Sauberer M . Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with C-Metoclopramide PET. J Nucl Med. 2019; 61(7):1050-1057. PMC: 7383073. DOI: 10.2967/jnumed.119.237198. View

Deo A, Borson S, Link J, Domino K, Eary J, Ke B . Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease. J Nucl Med. 2014; 55(7):1106-11. PMC: 4691246. DOI: 10.2967/jnumed.113.130161. View

Andersson M, Johansson L, Eckerman K, Mattsson S . IDAC-Dose 2.1, an internal dosimetry program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms. EJNMMI Res. 2017; 7(1):88. PMC: 5668221. DOI: 10.1186/s13550-017-0339-3. View

van Assema D, Lubberink M, Bauer M, van der Flier W, Schuit R, Windhorst A . Blood-brain barrier P-glycoprotein function in Alzheimer's disease. Brain. 2011; 135(Pt 1):181-9. DOI: 10.1093/brain/awr298. View

Bauer M, Tournier N, Langer O . Imaging P-Glycoprotein Function at the Blood-Brain Barrier as a Determinant of the Variability in Response to Central Nervous System Drugs. Clin Pharmacol Ther. 2019; 105(5):1061-1064. PMC: 6491962. DOI: 10.1002/cpt.1402. View

Kreisl W, Liow J, Kimura N, Seneca N, Zoghbi S, Morse C . P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J Nucl Med. 2010; 51(4):559-66. PMC: 2856602. DOI: 10.2967/jnumed.109.070151. View

Sasongko L, Link J, Muzi M, Mankoff D, Yang X, Collier A . Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther. 2005; 77(6):503-14. DOI: 10.1016/j.clpt.2005.01.022. View

Van der Aart J, Hallett W, Rabiner E, Passchier J, Comley R . Radiation dose estimates for carbon-11-labelled PET tracers. Nucl Med Biol. 2011; 39(2):305-14. DOI: 10.1016/j.nucmedbio.2011.08.005. View

Argikar U, Gomez J, Ung D, Parkman H, Nagar S . Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies. Drug Metab Dispos. 2010; 38(8):1295-307. DOI: 10.1124/dmd.110.033357. View

10.

. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP. 2007; 37(2-4):1-332. DOI: 10.1016/j.icrp.2007.10.003. View

11.

Bateman D, Kahn C, Davies D . The pharmacokinetics of metoclopramide in man with observations in the dog. Br J Clin Pharmacol. 1980; 9(4):371-7. PMC: 1429975. DOI: 10.1111/j.1365-2125.1980.tb01064.x. View

12.

Giacomini K, Huang S, Tweedie D, Benet L, Brouwer K, Chu X . Membrane transporters in drug development. Nat Rev Drug Discov. 2010; 9(3):215-36. PMC: 3326076. DOI: 10.1038/nrd3028. View

13.

Pichler V, Ozenil M, Bamminger K, Vraka C, Hacker M, Langer O . Pitfalls and solutions of the fully-automated radiosynthesis of [C]metoclopramide. EJNMMI Radiopharm Chem. 2019; 4(1):31. PMC: 6920278. DOI: 10.1186/s41181-019-0083-2. View

14.

Bauer M, Bamminger K, Pichler V, Weber M, Binder S, Maier-Salamon A . Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects. Clin Pharmacol Ther. 2020; 109(3):754-761. PMC: 7983943. DOI: 10.1002/cpt.2052. View

15.

Tournier N, Bauer M, Pichler V, Nics L, Klebermass E, Bamminger K . Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate C-Metoclopramide Assessed with PET Imaging in Humans. J Nucl Med. 2019; 60(7):985-991. PMC: 6604692. DOI: 10.2967/jnumed.118.219972. View

17.

Feldmann M, Asselin M, Liu J, Wang S, McMahon A, Anton-Rodriguez J . P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol. 2013; 12(8):777-85. DOI: 10.1016/S1474-4422(13)70109-1. View

18.

Auvity S, Caille F, Marie S, Wimberley C, Bauer M, Langer O . P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of C-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates. J Nucl Med. 2018; 59(10):1609-1615. DOI: 10.2967/jnumed.118.210104. View

19.

Tournier N, Stieger B, Langer O . Imaging techniques to study drug transporter function in vivo. Pharmacol Ther. 2018; 189:104-122. DOI: 10.1016/j.pharmthera.2018.04.006. View

20.

Hellstern A, Hellenbrecht D, Saller R, Gatzen M, Achtert G, Brockmann P . Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis. Eur J Clin Pharmacol. 1993; 45(5):415-8. DOI: 10.1007/BF00315511. View