Document Detail


Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS).
MedLine Citation:
PMID:  10554096     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To investigate whether d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) functions as an inhibitor of P-glycoprotein (P-gp), the multidrug resistance transporter. METHODS: Two assays were used to measure the function of TPGS on P-gp function. First, we examined the ability of TPGS to modulate the cytotoxicity of established, cytotoxic, P-glycoprotein substrates. Parental NIH 3T3 cells and NIH 3T3 cells transfected with the human MDR1 cDNA (G185) were exposed to doxorubicin, paclitaxel, colchicine, vinblastine and 5-fluorouracil (5FU) in the presence or absence of TPGS. Cytotoxicity was assessed with the MTT assay. Second, polarized transport of the P-gp substrates rhodamine 123 (R123), paclitaxel and vinblastine was measured using the human intestinal HCT-8 and Caco-2 cell lines grown in Transwell dishes. Drug flux was measured by liquid scintillation counting or fluorescence spectroscopy of the media. RESULTS: G185 cells were 27-135 fold more resistant to the cytotoxic drugs doxorubicin, vinblastine, colchicine and paclitaxel than the parental NIH 3T3 cells. In contrast 5FU, which is not a P-gp substrate, is equally cytotoxic to parental and G185 cells. Co-administration of TPGS enhanced the cytotoxicity of doxorubicin, vinblastine, paclitaxel, and colchicine in the G185 cells to levels comparable to the parental cells. TPGS did not increase the cytotoxicity of 5FU in the G185 cells. Using a polarized epithelial cell transport assay, TPGS blocked P-gp mediated transport of R123 and paclitaxel in a dose responsive manner. CONCLUSIONS: These data demonstrate that TPGS acts as a reversal agent for P-glycoprotein mediated multidrug resistance and inhibits P-gp mediated drug transport. These results suggest that enhanced oral bioavailability of drugs co-administered with TPGS may, in part, be due to inhibition of P-glycoprotein in the intestine.
Authors:
J M Dintaman; J A Silverman
Related Documents :
2422786 - Accumulation and efflux of nickel from cultured pneumocytes.
12069596 - Real-time monitoring of p-glycoprotein activation in living cells.
19409796 - Design, synthesis and evaluations of acridone derivatives using candida albicans--searc...
15590186 - Multidrug-resistant hela cells overexpressing mrp1 exhibit sensitivity to cell killing ...
24195506 - Prognostic implication of tim-3 in clear cell renal cell carcinoma.
23288076 - The big gene is required for auxin-mediated organ growth in arabidopsis.
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pharmaceutical research     Volume:  16     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  1999 Oct 
Date Detail:
Created Date:  1999-12-23     Completed Date:  1999-12-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1550-6     Citation Subset:  IM    
Affiliation:
Division of Drug Transport, AvMax, Inc. Berkeley, California 94710, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
Antimetabolites, Antineoplastic / pharmacology
Antineoplastic Agents, Phytogenic / metabolism
Blotting, Western
Cell Survival / drug effects
Coloring Agents
Cyclosporine / metabolism
Fluorouracil / toxicity
Immunosuppressive Agents / metabolism
Mice
Micelles
P-Glycoprotein / antagonists & inhibitors*
Paclitaxel / metabolism
Polyethylene Glycols
Rhodamine 123
Vinblastine / metabolism
Vitamin E / analogs & derivatives*,  pharmacology
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents, Phytogenic; 0/Coloring Agents; 0/Immunosuppressive Agents; 0/Micelles; 0/P-Glycoprotein; 0/Polyethylene Glycols; 1406-18-4/Vitamin E; 33069-62-4/Paclitaxel; 51-21-8/Fluorouracil; 59865-13-3/Cyclosporine; 62669-70-9/Rhodamine 123; 865-21-4/Vinblastine; 9002-96-4/alpha-tocopheryl polyethylene glycol succinate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Distribution of a 20-mer phosphorothioate oligonucleotide, CGP69846A (ISIS 5132), into airway leukoc...
Next Document:  Oral mucosal permeability and stability of transforming growth factor beta-3 in vitro.