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The blood-brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2-25 Gy followed by 10 mg kg-1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg -1), or with fractionated irradiation (4 x 5 Gy) followed by CsA (10 mg kg-1) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [11C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11C]carvedilol uptake dose-dependently in both hemispheres, but more (P11C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.

1 Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support evelopment of strategies, which will improve drug delivery to the brain. [C-11] 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 beta-receptor antagonist carvedilol is a P-gp substrate with a log P = 2.0, and can be labeled with [C-11]. The aim of this study was to determine whether the P-gp substrate [C-11] carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. 2 Cellular [C-11] carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC4/Adr cells. 3 Ex vivo [C-11] carvedilol biodistribution studies showed that [C-11] carvedilol uptake in the brain was increased by CsA. [C-11] carvedilol uptake in other organs was not affected by CsA. 4 Autoradiography studies of rat brains showed that [ C-11] carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [C-11] carvedilol uptake. 5 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 [C-11] carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [C-11] carvedilol is not trapped in the brain. Brain DV of [C-11] 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 [C-11] verapamil less CsA was needed to reach maximal DV, suggesting that [C-11] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.

1 Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support evelopment of strategies, which will improve drug delivery to the brain. [C-11] 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 beta-receptor antagonist carvedilol is a P-gp substrate with a log P = 2.0, and can be labeled with [C-11]. The aim of this study was to determine whether the P-gp substrate [C-11] carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB.2 Cellular [C-11] carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC4/Adr cells.3 Ex vivo [C-11] carvedilol biodistribution studies showed that [C-11] carvedilol uptake in the brain was increased by CsA. [C-11] carvedilol uptake in other organs was not affected by CsA.4 Autoradiography studies of rat brains showed that [ C-11] carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [C-11] carvedilol uptake.5 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 [C-11] carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [C-11] carvedilol is not trapped in the brain. Brain DV of [C-11] 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 [C-11] verapamil less CsA was needed to reach maximal DV, suggesting that [C-11] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.

1 Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support evelopment of strategies, which will improve drug delivery to the brain. [C-11] 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 beta-receptor antagonist carvedilol is a P-gp substrate with a log P = 2.0, and can be labeled with [C-11]. The aim of this study was to determine whether the P-gp substrate [C-11] carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. 2 Cellular [C-11] carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC4/Adr cells. 3 Ex vivo [C-11] carvedilol biodistribution studies showed that [C-11] carvedilol uptake in the brain was increased by CsA. [C-11] carvedilol uptake in other organs was not affected by CsA. 4 Autoradiography studies of rat brains showed that [ C-11] carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [C-11] carvedilol uptake. 5 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 [C-11] carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [C-11] carvedilol is not trapped in the brain. Brain DV of [C-11] 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 [C-11] verapamil less CsA was needed to reach maximal DV, suggesting that [C-11] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.