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rdf:type |
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lifeskim:mentions |
umls-concept:C0005508,
umls-concept:C0021853,
umls-concept:C0144576,
umls-concept:C0205177,
umls-concept:C0221102,
umls-concept:C0221908,
umls-concept:C0242643,
umls-concept:C0439801,
umls-concept:C0442027,
umls-concept:C0678133,
umls-concept:C1314792
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pubmed:issue |
5
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pubmed:dateCreated |
1997-4-7
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pubmed:abstractText |
In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(-/-) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(-/-) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(-/-) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(-/-) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(-/-) mice. Biliary excretion was not significantly different in wt and mdr1a(-/-) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(-/-) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-1403041,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-1680366,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-1974900,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2122232,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2207294,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2217211,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2432605,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2444983,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2463300,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2471060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2563168,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-2894894,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-3380797,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-3472246,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-41074,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-4660629,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-500733,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-6541914,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7494563,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7627725,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7628049,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7636546,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7850926,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7910522,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7913410,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7923194,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-7923556,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-8100632,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-8151326,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-8616858,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-8667431,
http://linkedlifedata.com/resource/pubmed/commentcorrection/9050899-8922756
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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 |
Mar
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
4
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pubmed:volume |
94
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2031-5
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:9050899-Administration, Oral,
pubmed-meshheading:9050899-Animals,
pubmed-meshheading:9050899-Bile,
pubmed-meshheading:9050899-Biological Availability,
pubmed-meshheading:9050899-Drug Resistance, Multiple,
pubmed-meshheading:9050899-Feces,
pubmed-meshheading:9050899-Intestinal Mucosa,
pubmed-meshheading:9050899-Intestines,
pubmed-meshheading:9050899-Mice,
pubmed-meshheading:9050899-Mice, Transgenic,
pubmed-meshheading:9050899-P-Glycoprotein,
pubmed-meshheading:9050899-Paclitaxel
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pubmed:year |
1997
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pubmed:articleTitle |
Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine.
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pubmed:affiliation |
Department of Clinical Chemistry, Antoni van Leeuwenhoek Huis, The Netherlands Cancer Institute, Amsterdam.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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