Linked Life Data

11395570

Source:http://linkedlifedata.com/resource/pubmed/id/11395570

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2001-6-7
pubmed:abstractText
Irinotecan (CPT-11) is a camptothecin analog with low (about 10--20%) and variable oral bioavailability in animal models. Here, Caco-2 cells were used to evaluate the transepithelial transport of CPT-11 and its metabolites. Caco-2 cells demonstrated significant expression of P-glycoprotein (P-gp), multidrug resistance-associated protein and canalicular multispecific organic anion transporter. Both the lactone and carboxylate forms of CPT-11 and SN-38 were actively transported across the cell monolayers, mainly by the apical-localized P-gp pump. Cellular permeability of CPT-11 at a concentration of 17 microM converted from active to passive-diffusional transport between the 2 and 6 h exposure time points. Antiproliferative effects of CPT-11 were related to permeability of the lactone form, whereas for SN-38 efficacy was dependent on lactone accumulation. Exposure of CPT-11 with cyclosporin A significantly enhanced its efficacy, whereas this was not observed with verapamil and R101933. In contrast, SN-38 efficacy decreased in the presence of P-gp inhibitors due to active transport toward the basolateral side, thereby reducing drug accumulation. Hence, multiple-active transport systems could be demonstrated to be responsible for not only accumulation profiles but also cytotoxic efficacy of CPT-11 and SN-38 in the intestinal Caco-2 cells. It is suggested that CPT-11 might act in a time-dependent manner and that SN-38-mediated cytotoxicity relates to (dose-dependent) lactone kinetics. The results detailed in this report could contribute toward the development of a clinically useful oral formulation of CPT-11 with improved absorption characteristics and suggest that cyclosporin A is a suitable agent for further research of this concept.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0959-4973
pubmed:author
pubmed:issnType
Print
pubmed:volume
12
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
419-32
pubmed:dateRevised
2007-9-25
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells.
pubmed:affiliation
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek, and University Hospital Rotterdam, 3008 AE Rotterdam, The Netherlands.
pubmed:publicationType
Journal Article