Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients.
This study was designed to evaluate irinotecan (CPT-11) disposition and pharmacodynamics in the presence and absence of the broad-spectrum antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea graded > or =2 after receiving CPT-11 alone (350 mg/m(2) i.v. once every 3 weeks) received the same dose combined with oral neomycin at 1000 mg three times per day (days -2 to 5) in the second course. Neomycin had no effect on the systemic exposure of CPT-11 and its major metabolites (P > or = 0.22). However, it changed fecal beta-glucuronidase activity from 7.03 +/- 1.76 microg/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 = 0.033). Our findings indicate that bacterial beta-glucuronidase plays a crucial role in CPT-11-induced diarrhea without affecting enterocycling and systemic SN-38 levels.
Kehrer
D F
DF
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek and University Hospital Rotterdam, 3075 EA Rotterdam, the Netherlands. kehrer@vvdh.azr.nl
Sparreboom
A
A
Verweij
J
J
de Bruijn
P
P
Nierop
C A
CA
van de Schraaf
J
J
Ruijgrok
E J
EJ
de Jonge
M J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives; D018592:Cross-Over Studies; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan; D008875:Middle Aged; D009355:Neomycin / Q000627:therapeutic use*; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D009355:Neomycin; D002166:Camptothecin