Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen.
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.
Kurita
Akinobu
A
Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan. akinobu-kurita@yakult.co.jp
Kado
Shoichi
S
Matsumoto
Tsuneo
T
Asakawa
Naoyuki
N
Kaneda
Norimasa
N
Kato
Ikuo
I
Uchida
Kazumi
K
Onoue
Masaharu
M
Yokokura
Teruo
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D008297:Male; D010400:Penicillin G / Q000494:pharmacology; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013307:Streptomycin / Q000494:pharmacology*; D013997:Time Factors
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D005966:Glucuronidase; D010400:Penicillin G; D002166:Camptothecin; D013307:Streptomycin