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Reduced Gastrointestinal Toxicity Following Inhibition of the Biliary Excretion of Irinotecan and Its Metabolites by Probenecid in Rats

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Abstract

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.

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Horikawa, M., Kato, Y. & Sugiyama, Y. Reduced Gastrointestinal Toxicity Following Inhibition of the Biliary Excretion of Irinotecan and Its Metabolites by Probenecid in Rats. Pharm Res 19, 1345–1353 (2002). https://doi.org/10.1023/A:1020358910490

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