Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to acute gastrointestinal toxicity of doxorubicin.
OBJECTIVE
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.
Li
Jing
J
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Zhou
Shufeng
S
Huynh
Hung
H
Duan
Wei
W
Chan
Eli
E
D000208:Acute Disease; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D041981:Gastrointestinal Tract / Q000187:drug effects*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013754:Tetracyclines / Q000493:pharmacokinetics*
D001798:Blood Proteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3; D004317:Doxorubicin