JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Batrakova, E. V.
Right arrow Articles by Kabanov, A. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Batrakova, E. V.
Right arrow Articles by Kabanov, A. V.

Vol. 299, Issue 2, 483-493, November 2001

Mechanism of Pluronic Effect on P-Glycoprotein Efflux System in Blood-Brain Barrier: Contributions of Energy Depletion and Membrane Fluidization

Elena V. Batrakova, Shu Li, Sergey V. Vinogradov, Valery Yu Alakhov, Donald W. Miller and Alexander V. Kabanov

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska (E.V.B., S.L., S.V.V., D.W.M., A.V.K.); and Supratek Pharma Inc., Laval, Quebec, Canada (V.Y.A)

Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl-1,3,5-hexatriene for membrane microviscosity. Using 3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB.

0022-3565/01/2992-0483$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 CA Cancer J ClinHome page
X. Wang, L. Yang, Z. Chen, and D. M. Shin
Application of Nanotechnology in Cancer Therapy and Imaging
CA Cancer J Clin, March 1, 2008; 58(2): 97 - 110.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
T. M. Krupka, B. D. Weinberg, H. Wu, N. P. Ziats, and A. A. Exner
Effect of Intratumoral Injection of Carboplatin Combined with Pluronic P85 or L61 on Experimental Colorectal Carcinoma in Rats
Experimental Biology and Medicine, July 1, 2007; 232(7): 950 - 957.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
E. Garcion, A. Lamprecht, B. Heurtault, A. Paillard, A. Aubert-Pouessel, B. Denizot, P. Menei, and J.-P. Benoit
A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats.
Mol. Cancer Ther., July 1, 2006; 5(7): 1710 - 1722.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
K. Niimi, D. R. K. Harding, R. Parshot, A. King, D. J. Lun, A. Decottignies, M. Niimi, S. Lin, R. D. Cannon, A. Goffeau, et al.
Chemosensitization of Fluconazole Resistance in Saccharomyces cerevisiae and Pathogenic Fungi by a D-Octapeptide Derivative
Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1256 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. V. Batrakova, S. Li, V. Y. Alakhov, D. W. Miller, and A. V. Kabanov
Optimal Structure Requirements for Pluronic Block Copolymers in Modifying P-glycoprotein Drug Efflux Transporter Activity in Bovine Brain Microvessel Endothelial Cells
J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 845 - 854.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. A. Witt, J. D. Huber, R. D. Egleton, and T. P. Davis
Pluronic P85 Block Copolymer Enhances Opioid Peptide Analgesia
J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 760 - 767.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.