Linked Life Data

8917684

Source:http://linkedlifedata.com/resource/pubmed/id/8917684

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1996-12-23
pubmed:abstractText
Physiologically based pharmacokinetic modeling (PBPK) and gas uptake experiments have been used by researchers to demonstrate the competitive inhibition mechanism between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE). Expanding on their work, we showed that this pharmacokinetic interaction was absent at levels of 100 ppm or less of either chemical in gas uptake systems. In this study, we further illustrate the presence of such an interaction threshold at the pharmacodynamic level by examining the interaction effect of either chemical on the other's ability to bind and deplete hepatic glutathione (GSH) in Fischer 344 rats. However, at this end point, the pharmacodynamic interaction is complicated by the ability of the liver to resynthesize GSH in response to its depletion. To quantitatively resolve the interaction effects on GSH content from the resynthesis effects, physiologically based pharmacodynamic (PBPD) modeling is applied. Initially, the PBPD model description of hepatic GSH kinetics was calibrated against previously published data and by gas uptake experiments conducted in our laboratory. Then, the model was used to determine the duration of the gas uptake exposure experiments by identifying the critical time point at which hepatic GSH is at a minimum in response to both chemicals. Subsequently, gas uptake experiments were designed following the PBPK/PD model predictions. In these model-directed experiments, DCE was the only chemical capable of significantly depleting hepatic GSH. The application of TCE to the rats at concentrations higher than 100 ppm obstructed the ability of DCE to deplete hepatic GSH. Since the metabolites of DCE bind to hepatic GSH, this obstruction signaled the presence of metabolic inhibition by TCE. However, TCE, at concentrations less than 100 ppm, was not effective in inhibiting DCE from significantly depleting hepatic GSH. The same observations were made when the ability of DCE to cause hepatic injury, as measured by aspartate aminotransferase serum activity, was assessed. Both conclusions validated the previous findings of the presence of the interaction threshold at the pharmacokinetic level.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0041-008X
pubmed:author
pubmed:issnType
Print
pubmed:volume
141
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
124-32
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Physiologically based pharmacodynamic modeling of an interaction threshold between trichloroethylene and 1,1-dichloroethylene in Fischer 344 rats.
pubmed:affiliation
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.