Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea.
OBJECTIVE
An antitumor camptothecin derivative CPT-11 has proven a broad spectrum of solid tumor malignancy, but its severe diarrhea has often limited its more widespread use. We have demonstrated from a rat model that intestinal beta-glucuronidase may play a key role in the development of CPT-11-induced delayed diarrhea by the deconjugation of the luminal SN-38 glucuronide, and the elimination of the intestinal microflora by antibiotics or dosing of TJ-14, a Kampo medicine that contains beta-glucuronidase inhibitor baicalin, exerted a protective effect. In the present study, we assessed the efficacy of several potential treatments in our rat model to clarify which is the most promising treatment for CPT-11-induced delayed diarrhea.


RESULTS
Oral dosing (twice daily from days -1 to 4) of streptomycin 20 mg/kg and penicillin 10 mg/kg (Str/Pen), neomycin 20 mg/kg and bacitracin 10 mg/kg (Neo/Bac), both of which inhibited almost completely the fecal beta-glucuronidase activity, or TJ-14 1,000 mg/kg improved the decrease in body weight and the delayed diarrhea symptoms induced by CPT-11 (60 mg/kg i.v. from days 1 to 4) to a similar extent. The efficacy was less but significant in activated charcoal (1,000 mg/kg p.o. twice daily from days -1 to 4). In a separate experiment using rats bearing breast cancer (Walker 256-TC), TJ-14, Neo/Bac, and charcoal at the same dose regimen improved CPT-11-induced intestinal toxicity without reducing CPT-11's antitumor activity. In contrast, oral dosing (twice a day) of cyclosporin A (50 mg/kg), a P-glycoprotein and cMOAT/MRP2 inhibitor or valproic acid (200 mg/kg), a UDP-glucuronosyltranferase inhibitor, exacerbated the intestinal toxicity without modifying CPT-11's antitumor activity.


CONCLUSIONS
The result clearly demonstrated the ability of Neo/Bac, Str/Pen, and TJ-14, less but significant ability of activated charcoal, to ameliorate CPT-11-induced delayed-onset diarrhea, suggesting the treatments decreasing the exposure of the intestines to the luminal SN-38 are valuable for improvement of CPT-11-induced intestinal toxicity. In contrast, the treatments affecting the biliary excretion of CPT-11 and its metabolites might have undesirable results.
Takasuna
K
K
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 16-13 Kita-kasai 1-chome, Edogawa-ku, 134-8630, Tokyo, Japan. takas0p3@daiichipharm.co.jp
Hagiwara
T
T
Watanabe
K
K
Onose
S
S
Yoshida
S
S
Kumazawa
E
E
Nagai
E
E
Kamataki
T
T
D000818:Animals; D000930:Antidiarrheals / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000627:therapeutic use; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007422:Intestines / Q000201:enzymology*; D000077146:Irinotecan; D008297:Male; D020835:Medicine, Kampo; D010406:Penicillins / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013307:Streptomycin / Q000627:therapeutic use
D000930:Antidiarrheals; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010406:Penicillins; C038044:baicalin; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin; D013307:Streptomycin