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Fasting protects against the side effects of irinotecan treatment but does not affect anti‐tumour activity in mice
Author(s) -
Huisman Sander A,
Bruijn Peter,
Ghobadi MoghaddamHelmantel Inge M,
IJzermans Jan N M,
Wiemer Erik A C,
Mathijssen Ron H J,
Bruin Ron W F
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13317
Subject(s) - irinotecan , medicine , active metabolite , colorectal cancer , pharmacokinetics , adverse effect , metabolite , sn 38 , pharmacology , side effect (computer science) , gastroenterology , chemotherapy , cancer , endocrinology , computer science , programming language
Background The main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan‐induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti‐tumour activity in mice. Experimental Approach Male BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and fasted groups after which they were treated with irinotecan. Weight and adverse side effects were recorded daily. At the end of the experiment, tumours were resected and weighed, and concentrations of irinotecan and its active metabolite SN‐38 were determined in plasma and tumour. Key Results Fasting prevented the diarrhoea and visible signs of discomfort induced by irinotecan. Ad libitum fed animals developed leucopenia compared with untreated controls, whereas fasted mice did not. Irinotecan suppressed tumour growth equally in both treated groups, compared with untreated controls. Levels of the active irinotecan metabolite SN‐38 9 (calculated as AUC values) were significantly lower in fasted mice in both plasma and liver, but not in tumour tissue. Conclusions and Implications Fasting protected against irinotecan‐induced side effects without interfering with its anti‐tumour efficacy. Fasting induced a lower systemic exposure to SN‐38, which may explain the absence of adverse side effects, while tumour levels of SN‐38 remained unchanged. These data offer important new approaches to improve treatment with irinotecan in patients.