Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET

Syvänen, Stina; Blomquist, Gunnar; Sprycha, M.; Höglund, A. Urban; Roman, Magnus; Eriksson, Olof; Hammarlund‐Udenaes, Margareta; Långström, Bengt; Bergström, Mats

doi:10.1016/j.neuroimage.2006.05.047

Cited by 52 publications

(54 citation statements)

References 24 publications

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“…11 C]verapamil as P-gp substrate in patients (Hendrikse et al, 1998(Hendrikse et al, , 1999Bart et al, 2003Bart et al, , 2005Syvanen et al, 2006;Takano et al, 2006). Future studies should elucidate if these results can be extrapolated to the human setting.…”

Section: Discussionmentioning

confidence: 99%

“…At present the concept of efflux pump inhibition is most frequently studied for P-gp. Studies in rodents have shown that P-gp function can be inhibited with cyclosporin A (CsA) (Hendrikse et al, 1998(Hendrikse et al, , 1999Syvanen et al, 2006). To circumvent toxic side effects of CsA in patients, therapies that influence P-gp function could be utilised, such as radiotherapy.…”

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confidence: 99%

“…11 C]carvedilol (Hendrikse et al, 1999;Bart et al, 2003Bart et al, , 2005Syvanen et al, 2006;Takano et al, 2006). Other approaches like the 111 In-labelled 15D3 monoclonal anti-P-gp has been used to visualise P-gp expression (van Eerd et al, 2006).…”

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confidence: 99%

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Irradiation of rat brain reduces P-glycoprotein expression and function

et al. 2007

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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 À1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg À1 ), or with fractionated irradiation (4 Â 5 Gy) followed by CsA (10 mg kg À1 ) 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 [ 11 C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11 C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11 C]carvedilol uptake dose-dependently in both hemispheres, but more (Po0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [ 11 C]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.

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Irradiation of rat brain reduces P-glycoprotein expression and function

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“…[ 11 C]Verapamil is the most frequently used PET radioligand for P-gp studies (Hendrikse et al, 1999;Bart et al, 2003;Sasongko et al, 2005;Lee et al, 2006;Syvänen et al, 2006 (Doze et al, 2000;Bart et al, 2005;de Vries et al, 2005;Lazarova et al, 2008;Zoghbi et al, 2008). Some radioligands shown to be P-gp substrates in rodents are nonetheless taken up by the brain in primates, indicating that there may be species differences in P-gp function.…”

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Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

Syvänen¹,

Lindhe²,

Palner³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; and minipigs than in rats and guinea pigs. For example, the brainto-plasma ratio of [ 11 C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.

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“…Also, several studies have shown that the effect of Pgp inhibitors is rapid, and the Pgp function is promptly restored on the elimination of the inhibitors. 21,22 Our study showed a rapid decrease in the radioactivity of the whole brain soon after the infusion of Pgp inhibitor was terminated, despite the maintenance of the serum concentration of CS (data not shown). Therefore, a novel Pgp inhibitor with enhanced affinity and a longer half-life for binding Pgp will be required.…”

Section: Fig 2 T1-weighted Mr Images (Axial Viewmentioning

confidence: 69%

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

Shin¹,

Chu

Shin

et al. 2015

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-[11 C]-verapamil

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Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET

Cited by 52 publications

References 24 publications

Irradiation of rat brain reduces P-glycoprotein expression and function

Irradiation of rat brain reduces P-glycoprotein expression and function

Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

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Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET

Cited by 52 publications

References 24 publications

Irradiation of rat brain reduces P-glycoprotein expression and function

Irradiation of rat brain reduces P-glycoprotein expression and function

Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[11C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy

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Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[¹¹C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy