Linked Life Data

15155559

Source:http://linkedlifedata.com/resource/pubmed/id/15155559

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2004-5-24
pubmed:abstractText
We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3'-hydroxypaclitaxel (C3'-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3'-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6 alpha-hydroxypaclitaxel (6 alpha-OHP) was the main metabolite, followed by C3'-OHP and C2-OHP. Among different cDNA-expressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3'-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3'-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3'-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6 alpha-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6 alpha-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
32
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
666-74
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15155559-Adolescent, pubmed-meshheading:15155559-Adult, pubmed-meshheading:15155559-Animals, pubmed-meshheading:15155559-Antineoplastic Agents, Phytogenic, pubmed-meshheading:15155559-Cytochrome P-450 Enzyme System, pubmed-meshheading:15155559-Enzyme Inhibitors, pubmed-meshheading:15155559-Flavonoids, pubmed-meshheading:15155559-Humans, pubmed-meshheading:15155559-Isoenzymes, pubmed-meshheading:15155559-Kinetics, pubmed-meshheading:15155559-Male, pubmed-meshheading:15155559-Microsomes, Liver, pubmed-meshheading:15155559-Paclitaxel, pubmed-meshheading:15155559-Rats, pubmed-meshheading:15155559-Rats, Wistar, pubmed-meshheading:15155559-Species Specificity, pubmed-meshheading:15155559-Swine, pubmed-meshheading:15155559-Swine, Miniature, pubmed-meshheading:15155559-Taxoids, pubmed-meshheading:15155559-Troleandomycin
pubmed:year
2004
pubmed:articleTitle
Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs.
pubmed:affiliation
National Institute of Public Health, Srobárova 48, 100 42 Prague 10, Czech Republic. rvaclavikova@szu.cz
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't