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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2000-1-4
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pubmed:abstractText |
1 The kinetics and nature of equilibrium binding were used to characterize the molecular interaction of the anthranilic acid derivative [3H]-XR9576 with the multidrug resistance P-glycoprotein (P-gp). XR9576 displayed specific high-affinity binding to P-gp (Bmax = 275 pmol mg-1, Kd = 5.1 nM). The transport substrates [3H]-vinblastine and [3H]-paclitaxel displayed 4 fold and 20 fold lower affinity respectively for P-gp. The duration of action of XR9576 with P-gp was increased in comparison to that of vinblastine which displayed a slower rate of association and a faster dissociation rate. 2 The relative affinities of several modulators and transport substrates to interact with P-gp were determined from displacement drug equilibrium binding assays. Vinblastine and paclitaxel could only fractionally displace [3H]-XR9576 binding, displaying Ki values significantly different from their measured Kd values. This suggests a non-competitive interaction between XR9576 and the P-gp substrates vinblastine and paclitaxel. 3 XR9576 was shown to be a potent modulator of P-gp mediated [3H]-vinblastine and [3H]-paclitaxel transport as it increased the steady-state accumulation of these cytotoxics in CHrB30 cells to levels observed in non-P-gp-expressing AuxB1 cells (EC50 = 487+/-50 nM). This inhibition of drug transport is not mediated through competition for transport since [3H]-XR9576 accumulation was not influenced by P-gp expression or function. 4 These results demonstrate that the P-gp modulator XR9576 exhibits greater selectivity, duration of inhibition and potency of interaction with this transporter than any other reported modulators. Several lines of evidence suggest that XR9576 inhibits P-gp function by binding at a site which is distinct from the site of interaction of transport substrates. The two sites may be classified as serving modulatory or transport functions.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-1355667,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-1358068,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-1670642,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-1678313,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-2564428,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-2834977,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-4202581,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-6137059,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-6467200,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-66232,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-686171,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7214365,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7598747,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7744732,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7772017,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7901214,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7909520,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-7911680,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-8401922,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-8402633,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-8634345,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-8713080,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-8799879,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-9117087,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-9375975,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-9698071,
http://linkedlifedata.com/resource/pubmed/commentcorrection/10510451-9764579
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0007-1188
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
128
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
403-11
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:10510451-Adenosine Triphosphate,
pubmed-meshheading:10510451-Animals,
pubmed-meshheading:10510451-Antineoplastic Agents, Phytogenic,
pubmed-meshheading:10510451-CHO Cells,
pubmed-meshheading:10510451-Cell Membrane,
pubmed-meshheading:10510451-Cricetinae,
pubmed-meshheading:10510451-Drug Resistance, Neoplasm,
pubmed-meshheading:10510451-Kinetics,
pubmed-meshheading:10510451-P-Glycoproteins,
pubmed-meshheading:10510451-Paclitaxel,
pubmed-meshheading:10510451-Protein Binding,
pubmed-meshheading:10510451-Quinolines,
pubmed-meshheading:10510451-Vinblastine
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pubmed:year |
1999
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pubmed:articleTitle |
The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein.
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pubmed:affiliation |
Nuffield Department of Clinical Biochemistry & Cellular Science, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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