Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood−Brain Barrier in Vitro and in Situ

2005 ◽  
Vol 48 (3) ◽  
pp. 832-838 ◽  
Author(s):  
Antonie Rice ◽  
Yanbin Liu ◽  
Mary Lou Michaelis ◽  
Richard H. Himes ◽  
Gunda I. Georg ◽  
...  
Keyword(s):  
Chemical Modification ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain

scholarly journals Borneol Depresses P-Glycoprotein Function by a NF-κB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model

2015 ◽  
Vol 16 (11) ◽  
pp. 27576-27588 ◽  
Author(s):  
Xiang Fan ◽  
Lijuan Chai ◽  
Han Zhang ◽  
Yuefei Wang ◽  
Boli Zhang ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
In Vitro Model ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Vitro Model

Challenges of Using In Vitro Data for Modeling P-Glycoprotein Efflux in the Blood-Brain Barrier

2013 ◽  
Vol 31 (1) ◽  
pp. 1-19 ◽  
Author(s):  
Noora Sjöstedt ◽  
Hanna Kortejärvi ◽  
Heidi Kidron ◽  
Kati-Sisko Vellonen ◽  
Arto Urtti ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?

2021 ◽  
pp. 0271678X2110454
Author(s):  
Louise Breuil ◽  
Solène Marie ◽  
Sébastien Goutal ◽  
Sylvain Auvity ◽  
Charles Truillet ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pet Imaging ◽  
Brain Barrier ◽  
Maximal Response ◽  
Half Maximum ◽  
Partial Inhibition ◽  
P Glycoprotein ◽  
Blood Brain

Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. In vitro, the half-maximum inhibitory concentration (IC50) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [11C]verapamil (44 nM), [11C] N-desmethyl-loperamide (19 nM) or [11C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [11C]metoclopramide, achieved using 1 mg/kg tariquidar ( in vivo IC50 = 82 nM in plasma), increased brain exposure by 2.1-fold for [11C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [11C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the “avid” substrate [11C] N-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the “vulnerability” to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their “avidity” (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.

scholarly journals Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

2010 ◽  
Vol 55 (2) ◽  
pp. 502-507 ◽  
Author(s):  
Liang Jin ◽  
Jian Li ◽  
Roger L. Nation ◽  
Joseph A. Nicolazzo
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Inflammation ◽  
Brain Barrier ◽  
Brain Uptake ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Colistin Sulfate ◽  
The Brain ◽  
Concentration Ratios

ABSTRACTThe aim of this study was to investigate the factors limiting the blood-brain barrier (BBB) transport of colistin in healthy mice and to assess the impact of systemic inflammation on the transport of this antibiotic across the BBB. Colistin sulfate (40 mg/kg) was administered subcutaneously to Swiss outbred mice as single and multiple doses to determine any relationship between brain uptake and plasma concentrations of colistin. To assess the effect of P-glycoprotein (P-gp) on BBB transport, colistin sulfate (5 mg/kg) was concomitantly administered intravenously with PSC833 or GF120918 (10 mg/kg). Systemic inflammation was induced by three intraperitoneal injections of lipopolysaccharide (LPS; 3 mg/kg), and BBB transport of colistin was subsequently measured following subcutaneous administration and by anin situbrain perfusion. The brain uptake of colistin was low following single and multiple subcutaneous doses, with brain-to-plasma concentration ratios ranging between 0.021 and 0.037, and this was not significantly enhanced by coadministration of GF120918 or PSC833 (P> 0.05). LPS significantly increased the brain uptake of subcutaneously administered colistin with area under the brain concentration time curve (AUCbrain) values of 11.7 ± 2.7 μg·h/g and 4.0 ± 0.3 μg·h/g for LPS- and saline-treated mice, respectively (mean ± standard deviation). Similarly,in situperfusion of colistin led to higher antibiotic brain concentrations in LPS-treated animals than in saline-treated animals, with colistin brain-to-perfusate concentration ratios of 0.019 ± 0.001 and 0.014 ± 0.001, respectively. This study demonstrates that the BBB transport of colistin is negligible in healthy mice; however, brain concentrations of colistin can be significantly enhanced during systemic inflammation, as might be observed in infected patients.

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