Effect of a P-glycoprotein inhibitor, cyclosporin A, on the disposition in rodent brain and blood of the 5-HT1A receptor radioligand, [11C](R)-(––)-RWAY

Synapse ◽  
2006 ◽  
Vol 61 (2) ◽  
pp. 96-105 ◽  
Author(s):  
Jeih-San Liow ◽  
Shuiyu Lu ◽  
Julie A. McCarron ◽  
Jinsoo Hong ◽  
John L. Musachio ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Rodent Brain ◽  
P Glycoprotein

Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone

2006 ◽  
Vol 309 (1-2) ◽  
pp. 81-86 ◽  
Author(s):  
Mingji Jin ◽  
Tsutomu Shimada ◽  
Koichi Yokogawa ◽  
Masaaki Nomura ◽  
Yukio Kato ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Oral Bioavailability ◽  
P Glycoprotein

scholarly journals Functional characterization of a glycine 185-to-valine substitution in human P-glycoprotein by using a vaccinia-based transient expression system.

1996 ◽  
Vol 7 (10) ◽  
pp. 1485-1498 ◽  
Author(s):  
M Ramachandra ◽  
S V Ambudkar ◽  
M M Gottesman ◽  
I Pastan ◽  
C A Hrycyna
Keyword(s):  
Drug Resistance ◽  
Atpase Activity ◽  
Cyclosporin A ◽  
Transient Expression ◽  
Expression System ◽  
Rhodamine 123 ◽  
Wild Type ◽  
P Glycoprotein ◽  
Transient Expression System

Human P-glycoprotein (Pgp) is a 170-kDa plasma membrane protein that confers multidrug resistance to otherwise sensitive cells. A mutation in Pgp, G185-->V, originally identified as a spontaneous mutation, was shown previously to alter the drug resistance profiles in cell lines that are stably transfected with the mutant MDR1 cDNA and selected with cytotoxic agents. To understand the mechanism by which the V185 mutation leads to an altered drug resistance profile, we used a transient expression system that eliminates the need for drug selection to attain high expression levels and allows for the rapid characterization of many aspects of Pgp function and biosynthesis. The mutant and wild-type proteins were expressed at similar levels after 24-48 h in human osteosarcoma (HOS) cells by infection with a recombinant vaccinia virus encoding T7 RNA polymerase and simultaneous transfection with a plasmid containing MDR1 cDNA controlled by the T7 promoter. For both mutant and wild-type proteins, photolabeling with [3H]azidopine and [125I]iodoarylazidoprazosin, drug-stimulated ATPase activity, efflux of rhodamine 123, and accumulation of radiolabeled vinblastine and colchicine were evaluated. In crude membrane preparations from HOS cells, a higher level of basal Pgp-ATPase activity was observed for the V185 variant than for the wild-type, suggesting partial uncoupling of drug-dependent ATP hydrolysis by the mutant. Several compounds, including verapamil, nicardipine, tetraphenylphosphonium, and prazosin, stimulated ATPase activities of both the wild-type and mutant similarly, whereas cyclosporin A inhibited the ATPase activity of the mutant more efficiently than that of the wild-type. This latter observation explains the enhanced potency of cyclosporin A as an inhibitor of the mutant Pgp. No differences were seen in verapamil-inhibited rhodamine 123 efflux, but the rate of accumulation was slower for colchicine and faster for vinblastine in cells expressing the mutant protein, as compared with those expressing wild-type Pgp. We conclude that the G185-->V mutation confers pleiotropic alterations on Pgp, including an altered basal ATPase activity and altered interaction with substrates and the inhibitor cyclosporin A.

Identification of the synthetic surfactant nonylphenol ethoxylate: a P-glycoprotein substrate in human urine

1998 ◽  
Vol 274 (6) ◽  
pp. F1127-F1139 ◽  
Author(s):  
Jeffrey H. M. Charuk ◽  
Arthur A. Grey ◽  
Reinhart A. F. Reithmeier
Keyword(s):  
Cyclosporin A ◽  
Drug Transport ◽  
Mdck Cells ◽  
Chinese Hamster ◽  
Multidrug Resistant ◽  
The Body ◽  
Transepithelial Transport ◽  
Synthetic Surfactant ◽  
Nonylphenol Ethoxylate ◽  
P Glycoprotein

P-glycoprotein (Mdr1p) is an ATP-dependent drug efflux pump that is overexpressed in multidrug-resistant cells and some cancers. Mdr1p is also expressed in normal tissues like the kidney, where it can mediate transepithelial drug transport. A human urinary compound that reverses multidrug resistance and blocks [3H]azidopine photolabeling of P-glycoprotein was purified to homogeneity and identified by 1H-NMR and mass spectrometry as the synthetic surfactant nonylphenol ethoxylate (NPE). Multidrug-resistant Chinese hamster ovary (CHO) C5 cells accumulated less [3H]NPE than parental drug-sensitive Aux-B1 cells, and Mdr1p substrates, verapamil and cyclosporin A, increased this surfactant’s accumulation in C5 cells. NPE blocked the net transepithelial transport (basolateral to apical) of [3H]cyclosporin A in epithelia formed by Madin-Darby canine kidney (MDCK) cells. Net transepithelial transport (basal to apical) of [3H]NPE was demonstrated in MDCK cells and was inhibited by cyclosporin A. These findings show NPE is a Mdr1p substrate excreted into urine by kidney P-glycoprotein. NPE is a widely used surfactant and a known hormone disrupter that is readily absorbed orally or topically. The current findings indicate the function of kidney Mdr1p may be to eliminate exogenous compounds from the body.

P-Glycoprotein, not BCRP, Limits the Brain Uptake of [18F]Mefway in Rodent Brain

2015 ◽  
Vol 18 (2) ◽  
pp. 267-273 ◽  
Author(s):  
Jae Yong Choi ◽  
Jin Sook Song ◽  
Minkyung Lee ◽  
Woon-Ki Cho ◽  
Jin Chung ◽  
...  
Keyword(s):  
Brain Uptake ◽  
Rodent Brain ◽  
P Glycoprotein ◽  
The Brain

scholarly journals Molecular Interactions of Cyclosporin A with P-glycoprotein

1997 ◽  
Vol 272 (10) ◽  
pp. 6647-6652 ◽  
Author(s):  
Michel Demeule ◽  
Roland M. Wenger ◽  
Richard Béliveau
Keyword(s):  
Cyclosporin A ◽  
Molecular Interactions ◽  
P Glycoprotein
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