Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Li, Jing, Zhou, Shufeng, Huynh, Hung, Duan, Wei and Chan, Eli 2005, Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin, Pharmaceutical research, vol. 22, no. 11, pp. 1954-1963.

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Title Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin
Author(s) Li, Jing
Zhou, Shufeng
Huynh, Hung
Duan, Wei
Chan, Eli
Journal name Pharmaceutical research
Volume number 22
Issue number 11
Start page 1954
End page 1963
Publisher Springer Netherlands
Place of publication Delft, The Netherlands
Publication date 2005-11
ISSN 0724-8741
1573-904X
Keyword(s) COL-3
doxorubicin
gastrointestinal toxicity
matrix metalloproteinase inhibitor
pharmacokinetic interaction
Summary Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

Language eng
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Springer Science + Business Media, Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009173

Document type: Journal Article
Collection: School of Medicine
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