Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen

• Published in: Cancer chemotherapy and pharmacology 2011, Vol.67 (1), p.201-213
• Main Authors: Kurita, Akinobu, Kado, Shoichi, Matsumoto, Tsuneo, Asakawa, Naoyuki, Kaneda, Norimasa, Kato, Ikuo, Uchida, Kazumi, Onoue, Masaharu, Yokokura, Teruo
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - toxicity; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - toxicity; Cancer Research; CPT-11; diarrhea; Diarrhea - chemically induced; Diarrhea - prevention & control; Gastroenterology. Liver. Pancreas. Abdomen; Glucuronidase - antagonists & inhibitors; Glucuronidase - metabolism; Glucuronosyltransferase - drug effects; Glucuronosyltransferase - metabolism; intestinal absorption; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Irinotecan hydrochloride; Male; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Other diseases. Semiology; Penicillin G - pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Rats; Rats, Gunn; Rats, Wistar; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; streptomycin; Streptomycin - pharmacology; Time Factors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1310-4

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 β-glucuronidase (β-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 β-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 β-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 β-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.