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Discrepancies in the P-glycoprotein-Mediated Transport of 18F-MPPF: A Pharmacokinetic Study in Mice and Non-human Primates

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Abstract

Purpose

Several in vivo studies have found that the 5-HT1A PET radioligand 18F-MPPF is a substrate of rodent P-glycoprotein (P-gp). However, in vitro assays suggest that MPPF is not a substrate of human P-gp. We have now tested the influence of inhibiting P-gp on the brain kinetics of 18F-MPPF in mice and non-human primates.

Methods

We measured the peripheral kinetics (arterial input function, metabolism, free fraction in plasma (fP)) during 18F-MPPF brain PET scanning in baboons with or without cyclosporine A (CsA) infusion. We measured 3H-MPPF transport at the mouse BBB using in situ brain perfusion in P-gp/Bcrp deficient mice and after inhibiting P-gp with PSC833.

Results

There was an unexpected 1.9-fold increase in brain area under the curve in CsA-treated baboons (n = 4), with no change in radiometabolite-corrected arterial input. However, total volume of distribution corrected for fP (VT/fP) remained unchanged. In situ brain perfusion showed that P-gp restricted the permeability of the mouse BBB to 3H-MPPF while Bcrp did not.

Conclusion

These and previous in vitro results suggest that P-gp may not influence the permeability of human BBB to 18F-MPPF. However, CsA treatment increased 18F-MPPF free fraction, which is responsible for a misleading, P-gp unrelated enhanced brain uptake.

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Abbreviations

ABC:

ATP–binding cassette

AUC:

area under the curve

BBB:

blood–brain barrier

BCRP:

breast cancer resistance protein

CNS:

central nervous system

CsA:

cyclosporine A

fP :

free fraction (unbound) in plasma

HPLC:

high performance liquid chromatography

MDCK:

Madin-Darby canine kidney cells

MPPF:

4-fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide

PET:

positron emission tomography

PK:

pharmacokinetic

P-gp:

P-glycoprotein

VOI:

volume of interest

VT :

total distribution volume

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Acknowledgments and disclosures

We thank Dr. Alfred H. Schinkel (The Netherlands Cancer Institute, Amsterdam) for providing the Mdr1a/1b;Bcrp(−/−;−/−) mice and the MDCKII transfected cells. Statistical analyses were kindly performed by Dr. Marcel Debray. The English text was edited by Dr. Owen Parkes. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, 91401, France

    Nicolas Tournier, Marie-Anne Peyronneau, Sébastien Goutal, Frédéric Dolle, Michel Bottlaender, Wadad Saba & Héric Valette

  2. INSERM U705, CNRS UMR8206, Faculté de Pharmacie Université Paris Descartes Sorbonne Paris Cité, Université Paris Diderot, Paris, France

    Salvatore Cisternino & Jean-Michel Scherrmann

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  1. Nicolas Tournier
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Correspondence to Nicolas Tournier.

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Tournier, N., Cisternino, S., Peyronneau, MA. et al. Discrepancies in the P-glycoprotein-Mediated Transport of 18F-MPPF: A Pharmacokinetic Study in Mice and Non-human Primates. Pharm Res 29, 2468–2476 (2012). https://doi.org/10.1007/s11095-012-0776-7

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