Linked Life Data

15122071

Source:http://linkedlifedata.com/resource/pubmed/id/15122071

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2004-5-3
pubmed:abstractText
Thiocoraline is a potent new marine anti-cancer drug in vitro, which will be tested in phase I clinical studies shortly. To assess the biotransformation and the potential implications for human pharmacology and toxicology, the in vitro metabolism of thiocoraline was characterized using human plasma, human liver preparations, cytochrome P450 (CYP) and uridine diphosphoglucuronosyl transferase (UGT) supersomes and human cell lines. Thiocoraline is significantly metabolized by enzymes present in human plasma; t (1/2) shifted from 25.2 h in phosphate buffered saline to 4.3 h in human plasma. Using CYP supersomes it was shown that thiocoraline is mainly metabolized by CYP3A4, with CYP1A1, CYP2C8 and CYP2C9 playing a minor role in the biotransformation (<3%). Only minor glucuronidation was observed for thiocoraline by UGT1A1 and UGT1A9 and no glucuronidation was observed in human liver S9 fraction. In addition, no glucosidation and sulfation were observed for thiocoraline in human liver cytosol and S9 fraction. However, the metabolites formed by cytochrome P450 were further conjugated by UGT, glutathione-S-transferase (GST) and sulfotransferase (ST). In contrast to the CYP metabolism observed in supersomes, no effect could be observed from the CYP3A4 inhibitors on the cytotoxicity of thiocoraline in Hep G2 cells. However, this could be due to low CYP expression levels in the Hep G2 and IGROV-1 cell line. These results provide evidence that human CYP3A4 plays a major role in the metabolism of thiocoraline in vitro and that the metabolites formed by CYP are conjugated by the phase II enzymes UGT, ST and GST.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0167-6997
pubmed:author
pubmed:issnType
Print
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
241-51
pubmed:dateRevised
2009-11-3
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
In vitro characterization of the biotransformation of thiocoraline, a novel marine anti-cancer drug.
pubmed:affiliation
Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. E.F.A.Brandon@pharm.uu.nl
pubmed:publicationType
Journal Article, Comparative Study, In Vitro