Advances in Brief Modulation of Irinotecan-induced Diarrhea by Cotreatment with Neomycin in Cancer Patients

Abstract

This study was designed to evaluate irinotecan (CPT11) disposition and pharmacodynamics in the presence and absence of the broad-spectrum antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea graded >2 after receiving CPT-11 alone (350 mg/m i.v. once every 3 weeks) received the same dose combined with oral neomycin at 1000 mg three times per day (days 22 to 5) in the second course. Neomycin had no effect on the systemic exposure of CPT-11 and its major metabolites (P > 0.22). However, it changed fecal b-glucuronidase activity from 7.03 6 1.76 mg/h/mg (phenolphthalein assay) to undetectable levels and decreased fecal concentrations of the pharmacologically active metabolite SN-38. Although neomycin had no significant effect on hematological toxicity (P > 0.05), diarrhea ameliorated in six of seven patients (P 5 0.033). Our findings indicate that bacterial b-glucuronidase plays a crucial role in CPT-11-induced diarrhea without affecting enterocycling and systemic SN-38 levels. Introduction CPT-11 is an inhibitor of topoisomerase I, an enzyme responsible for variations in the topological form of DNA during replication and transcription. Unlike other clinically used camptothecin analogues, CPT-11 is a prodrug with very little inherent antitumor activity that needs to be hydrolyzed by a carboxylesterase to form the active metabolite SN-38 (Ref. 1; Fig. 1). SN-38 in its turn is efficiently metabolized by UDP glucuronosyltransferase 1A1 to form the inactive SN-38G (2). Myelosuppression and diarrhea are among the most common side effects of CPT-11 (3), regardless of the schedule of administration. Delayed-type diarrhea is defined as diarrhea occurring .24 h after CPT-11 administration and contrasts with the early-onset diarrhea that is acetylcholine mediated and can be prevented by atropine (4). CPT-11-induced delayed-type diarrhea has been reported to be severe (NCI-CTC grade 3–4) in ;25% of the patients (5). Moreover, even less severe diarrhea might influence continuation of therapy. The median onset of delayed-type diarrhea is day 5 after start of CPT-11 administration, and the median duration is 5 days. Delayed-type diarrhea necessitated hospitalization in 9% of the cycles for i.v. rehydration. There is no generally accepted prophylactic treatment for the delayed-type diarrhea. However, once diarrhea has occurred, a high-dose loperamide regimen renders this side effect man-

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@inproceedings{Kehrer2001AdvancesIB, title={Advances in Brief Modulation of Irinotecan-induced Diarrhea by Cotreatment with Neomycin in Cancer Patients}, author={Diederik F. S. Kehrer and Alex Sparreboom and Jaap Verweij and Peter de Bruijn and Corine A. Nierop and Jacqueline van de Schraaf and Elisabeth J. Ruijgrok and Maja J. A. de Jonge}, year={2001} }