Linked Life Data

11745902

Source:http://linkedlifedata.com/resource/pubmed/id/11745902

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2001-12-17
pubmed:abstractText
The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0142-2782
pubmed:author
pubmed:copyrightInfo
Copyright 2001 John Wiley & Sons, Ltd.
pubmed:issnType
Print
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1-14
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11745902-Administration, Oral, pubmed-meshheading:11745902-Animals, pubmed-meshheading:11745902-Antimetabolites, Antineoplastic, pubmed-meshheading:11745902-Area Under Curve, pubmed-meshheading:11745902-Colonic Neoplasms, pubmed-meshheading:11745902-Cytosol, pubmed-meshheading:11745902-Deoxycytidine, pubmed-meshheading:11745902-Dose-Response Relationship, Drug, pubmed-meshheading:11745902-Fluorouracil, pubmed-meshheading:11745902-Humans, pubmed-meshheading:11745902-Kidney, pubmed-meshheading:11745902-Male, pubmed-meshheading:11745902-Mice, pubmed-meshheading:11745902-Mice, Inbred BALB C, pubmed-meshheading:11745902-Mice, Nude, pubmed-meshheading:11745902-Neoplasm Transplantation, pubmed-meshheading:11745902-Prodrugs, pubmed-meshheading:11745902-Subcellular Fractions, pubmed-meshheading:11745902-Therapeutic Equivalency, pubmed-meshheading:11745902-Tissue Distribution, pubmed-meshheading:11745902-Tumor Cells, Cultured, pubmed-meshheading:11745902-Xenograft Model Antitumor Assays
pubmed:year
2001
pubmed:articleTitle
Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model.
pubmed:affiliation
Nippon Roche Research Centre, Kamakura, Kanagawa, Japan.
pubmed:publicationType
Journal Article, Comparative Study