Pharmacokinetics of P‐glycoprotein inhibition in the rat blood‐brain barrier

Syvänen, Stina; Hooker, Andrew C.; Rahman, Obaidur; Wilking, Helena; Blomquist, Gunnar; Långström, Bengt; Bergström, Mats; Hammarlund‐Udenaes, Margareta

doi:10.1002/jps.21359

Cited by 28 publications

(25 citation statements)

References 22 publications

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“…However, this is not a very likely explanation for the species differences seen in this study because the differences were already observed at the beginning of the PET scans, when most of the radioactivity originated from the intact radioligand. Previous studies focusing in more detail on the metabolism of [ (Tan et al, 1999;Luurtsema et al, 2005;Syvänen et al, 2008). Thus, metabolism and plasma protein binding were ruled out as explanations for the species differences.…”

Section: Syvä Nen Et Almentioning

confidence: 99%

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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319

271

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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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Section: Syvä Nen Et Almentioning

confidence: 99%

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

Self Cite

319

271

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“…The blood-CSF barrier is formed by the epithelium of the choroid plexus, which also contains transport proteins, such as ABCC1, that act as a barrier for certain drugs entering from the blood. This implies that specific inhibitors of P-gp and other drug transporters present in these barriers can be useful to increase the permeability of the blood-brain barrier and the blood-CSF barrier for anticancer drugs, which might enable the treatment with chemotherapy of primary brain tumors with an intact blood-brain barrier (157,158). Preclinical studies have shown that the central nervous system (CNS) penetration of anticancer drugs, which are transported by Pgp, such as paclitaxel (159), etoposide (160,161), doxorubicin, (162) and imatinib (163)(164)(165)(166), can indeed be improved by concomitant use of P-gp inhibitors, such as cyclosporin A, valspodar, elacridar and zosuquidar (13).…”

Section: Tissue Distribution: Blood Brain Barriermentioning

confidence: 99%

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Bansal¹,

Jaggi²,

Khar³

et al. 2009

J Pharm Pharm Sci

213

161

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Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

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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: 72%

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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Pharmacokinetics of P‐glycoprotein inhibition in the rat blood‐brain barrier

Cited by 28 publications

References 22 publications

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

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

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

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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Pharmacokinetics of P‐glycoprotein inhibition in the rat blood‐brain barrier

Cited by 28 publications

References 22 publications

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

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

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

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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Product

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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