Title : Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of beta-glucuronidase activity in intestinal lumen - Kurita_2011_Cancer.Chemother.Pharmacol_67_201 |
Author(s) : Kurita A , Kado S , Matsumoto T , Asakawa N , Kaneda N , Kato I , Uchida K , Onoue M , Yokokura T |
Ref : Cancer Chemother Pharmacol , 67 :201 , 2011 |
Abstract :
Irinotecan hydrochloride (CPT-11) is a useful drug for cancer chemotherapy but sometimes induces severe diarrhea clinically. CPT-11 is mainly activated to SN-38 by carboxylesterase (CES) and then detoxified to SN-38 glucuronide (SN-38G) by UDP-glucuronosyltransferase (UGT) in the liver. SN-38G is excreted via bile and de-conjugated to SN-38 by beta-glucuronidase (beta-GLU) in the intestinal content. In order to clarify the alleviative effect of antibiotics on CPT-11-induced diarrhea, we examined whether penicillin G and streptomycin (SM) alleviate CPT-11-induced delayed-onset diarrhea using three diarrheal models, i.e., Wistar rats with repeated dosing of CPT-11 (60 mg/kg/day i.v. for 4 consecutive days) and Wistar and Gunn rats with a single dosing of CPT-11 (200 and 20 mg/kg i.v., respectively). Gunn rats have an inherited deficiency of UGT1A and cannot conjugate SN-38 to SN-38G. Therefore, onset of CPT-11-induced diarrhea in Gunn rats is not affected by beta-GLU activity. SM alleviated diarrhea in all three diarrheal models. The alleviation of diarrhea by SM in Gunn rats indicated that the effect of SM occurred by a mechanism other than the inhibition of beta-GLU activity. SM decreased CPT-11 and/or SN-38 concentrations in intestinal tissues and alleviated epithelial damage from the ileum to colon. SM did not inhibit beta-GLU activity in the cecal content. SM also inhibited the intestinal absorption of CPT-11 and decreased CES activity and increased UGT activity in the intestinal epithelium. These findings indicated that SM decreased the exposure of CPT-11 and SN-38 to the intestinal epithelium by inhibiting the absorption of CPT-11 from the intestinal lumen and the change of CES and UGT activities in the intestinal epithelium and alleviated delayed-onset diarrhea. |
PubMedSearch : Kurita_2011_Cancer.Chemother.Pharmacol_67_201 |
PubMedID: 20354702 |
Kurita A, Kado S, Matsumoto T, Asakawa N, Kaneda N, Kato I, Uchida K, Onoue M, Yokokura T (2011)
Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of beta-glucuronidase activity in intestinal lumen
Cancer Chemother Pharmacol
67 :201
Kurita A, Kado S, Matsumoto T, Asakawa N, Kaneda N, Kato I, Uchida K, Onoue M, Yokokura T (2011)
Cancer Chemother Pharmacol
67 :201