Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats

Pharm Res. 2002 Sep;19(9):1345-53. doi: 10.1023/a:1020358910490.


Purpose: 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.

MeSH terms

  • Animals
  • Bile / drug effects
  • Bile / metabolism*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / antagonists & inhibitors*
  • Camptothecin / metabolism
  • Camptothecin / toxicity*
  • Digestive System / drug effects
  • Digestive System / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Irinotecan
  • Male
  • Probenecid / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Irinotecan
  • Probenecid
  • Camptothecin