Influence of P-Glycoprotein Inhibition or Deficiency at the Blood–Brain Barrier on 18F-2-Fluoro-2-Deoxy-d -glucose (18F-FDG) Brain Kinetics
Journal Title: The AAPS Journal - Year 2015, Vol 17, Issue 3
Abstract
The fluorinated d -glucose analog 18F-2-fluoro-2-deoxy-d -glucose (18F-FDG) is the most prevalent radiopharmaceutical for positron emission tomography (PET) imaging. P-Glycoprotein’s (P-gp, MDR1, and ABCB1) function in various cancer cell lines and tumors was shown to impact 18F-FDG incorporation, suggesting that P-gp function at the blood–brain barrier may also modulate 18F-FDG brain kinetics. We tested the influence of P-gp inhibition using the cyclosporine analog valspodar (PSC833; 5 μM) on the uptake of 18F-FDG in standardized human P-gp-overexpressing cells (MDCKII-MDR1). Consequences for 18F-FDG brain kinetics were then assessed using (i) 18F-FDG PET imaging and suitable kinetic modelling in baboons without or with P-gp inhibition by intravenous cyclosporine infusion (15 mg kg−1 h−1) and (ii) in situ brain perfusion in wild-type and P-gp/Bcrp (breast cancer resistance protein) knockout mice and controlled d -glucose exposure to the brain. In vitro, the time course of 18F-FDG uptake in MDR1 cells was influenced by the presence of valspodar in the absence of d -glucose but not in the presence of high d -glucose concentration. PET analysis revealed that P-gp inhibition had no significant impact on estimated brain kinetics parameters K1, k2, k3, VT, and CMRGlc. The lack of P-gp effect on in vivo18F-FDG brain distribution was confirmed in P-gp/Bcrp-deficient mice. P-gp inhibition indirectly modulates 18F-FDG uptake into P-gp-overexpressing cells, possibly through differences in the energetic cell level state. 18F-FDG is not a P-gp substrate at the BBB and 18F-FDG brain kinetics as well as estimated brain glucose metabolism are influenced by neither P-gp inhibition nor P-gp/Bcrp deficiencies in baboon and mice, respectively.
Authors and Affiliations
Nicolas Tournier, Wadad Saba, Sébastien Goutal, Philippe Gervais, Héric Valette, Jean-Michel Scherrmann, Michel Bottlaender, Salvatore Cisternino
Keywords
Related Articles
- EP ID EP680951
- DOI 10.1208/s12248-015-9739-3
- Views 55
- Downloads 0
Evaluating and Reporting the Immunogenicity Impacts for Biological Products—a Clinical Pharmacology Perspective
Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA’s clinical pharmacology review...
Oral bioavailability in pigs of a miconazole/Hydroxypropyl-γ-cyclodextrin/ L-tataric acid inclusion complex produced by supercritical carbon dioxide processing
The objective of this study was to determine the pharmacokinetic parameters of miconazole after oral administration of a miconazole/hydroxypropyl-γ-cyclodextrin(HPγCD)/ L-tartaric acid inclusion complex p...
Properties of thalidomide and its analogues: Implications for anticancer therapy
Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to medi...
Phosphorothioate Oligonucleotide Quantification by μ-Liquid Chromatography-Mass Spectrometry
Phosporothioate oligonucleotides represent an important class of therapeutic oligonucleotides, in which none-bridging oxygen atoms of the phosphate groups are replaced by sulfur. These oligonucleotides are designed to tr...
Marketplace Analysis of Conjugated Estrogens: Determining the Consistently Present Steroidal Content with LC-MS
The online version of this article (doi:10.1208/s12248-015-9805-x) contains supplementary material, which is available to authorized users.