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- Title
New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics.
- Authors
Bart, Joost; Dijkers, Eli C. F.; Wegman, Theodora D.; de Vries, Elisabeth G. E.; van der Graaf, Winette T. A.; Groen, Harry J. M.; Vaalburg, Willem; Willemsen, Antoon T. M.; Hendrikse, N. Harry
- Abstract
Imaging of P-glycoprotein (P-gp) function in the blood–brain barrier (BBB) may support development of strategies, which will improve drug delivery to the brain. [11C]verapamil has been developed as a positron emission tomography (PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The β-receptor antagonist carvedilol is a P-gp substrate with a log P=2.0, and can be labeled with [11C]. The aim of this study was to determine whether the P-gp substrate [11C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB.Cellular [11C]carvedilol accumulation in GLC4, GLC4/P-gp, and GLC4/Adr cells increased three-fold in the GLC4/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC4/Adr cells.Ex vivo [11C]carvedilol biodistribution studies showed that [11C]carvedilol uptake in the brain was increased by CsA. [11C]carvedilol uptake in other organs was not affected by CsA.Autoradiography studies of rat brains showed that [11C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [11C]carvedilol uptake.In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [11C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [11C]carvedilol is not trapped in the brain. Brain DV of [11C]carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg−1, no change in DV was found. Compared to [11C]verapamil less CsA was needed to reach maximal DV, suggesting that [11C]carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.British Journal of Pharmacology (2005) 145, 1045–1051. doi:10.1038/sj.bjp.0706283; published online 13 June 2005
- Subjects
P-glycoprotein; GLYCOPROTEINS; POSITRON emission tomography; BRAIN; PHARMACOKINETICS; BLOOD-brain barrier
- Publication
British Journal of Pharmacology, 2005, Vol 145, Issue 8, p1045
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0706283