Alteration of the Pharmacokinetics of COL-3, a Matrix Metalloproteinase Inhibitor, Due to Acute Gastrointestinal Toxicity of Doxorubicin
COL-3, doxorubicin, gastrointestinal toxicity, matrix metalloproteinase inhibitor, pharmacokinetic interaction
Digital Object Identifier (DOI)
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.
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Citation / Publisher Attribution
Pharmaceutical Research, v. 22, issue 11, p. 1954-1963
Scholar Commons Citation
Li, Jing; Zhou, Shufeng; Huynh, Hung; Duan, Wei; and Chan, Eli, "Alteration of the Pharmacokinetics of COL-3, a Matrix Metalloproteinase Inhibitor, Due to Acute Gastrointestinal Toxicity of Doxorubicin" (2005). Pharmacy Faculty Publications. 30.