Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats.
OBJECTIVE
To ameliorate the late-onset of severe gastrointestinal toxicity provoked by irinotecan (CPT-11), which may be related to the biliary excretion of CPT-11 and/or its metabolites.


METHODS
Effects of probenecid, an inhibitor of MRP2/ABCC2, on the biliary excretion and mucosal intestinal tissue concentration of CPT-11 and its metabolites were examined in rats. CPT-11-induced late-onset gastrointestinal toxicity was also evaluated.


RESULTS
Coadministration of probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38) and its glucuronide by half with a concomitant increase in their plasma concentration. When the dose of CPT-11, in the presence of probenecid, was set at half that in its absence, the plasma SN-38 concentration was maintained at the same level as the control, whereas the mucosal intestinal tissue concentration of SN-38 was reduced. Under this condition, CPT-11-induced watery diarrhea, changes in intestinal marker enzymes and body weight reduction were much less in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as that in the control.


CONCLUSIONS
Coadministration of probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.
Horikawa
Masato
M
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Yukio
Y
Sugiyama
Yuichi
Y
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D000077146:Irinotecan; D008297:Male; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000077146:Irinotecan; D011339:Probenecid; D002166:Camptothecin