Abstract 4627: Fasting reduces the systemic exposure to irinotecan and its active metabolite SN-38

Abstract

Abstract Limitations to the use of chemotherapeutic agents are the often severe adverse side-effects which may lead to early discontinuation of treatment. Most anticancer agents have a narrow therapeutic index. In previous work we have shown that 72 hours of fasting prior to treatment with a high dose of irinotecan prevents the occurrence of adverse side effects in C26 colon carcinoma bearing mice, while the antitumor activity is not abrogated. To elucidate the mechanism of fasting induced resistance against adverse side effects, we have examined the pharmacokinetics of irinotecan in 72 hours fasted mice in plasma and liver. Male BALB/c mice were divided into four groups (n=18/group). Two groups were fasted for 72 hours and two groups were fed ad libitum. After the fasting period, mice were fed ad libitum again. One group of ad libitum and fasted animals was treated with 50 mg/kg and the other with 100 mg/kg irinotecan intraperitoneally. Plasma and liver were collected at 1,4,8,12,24 and 48 hours after irinotecan injection. Tissues were homogenized in lithium heparinized plasma and concentrations of irinotecan (CPT-11) and the active metabolite SN-38 were determined using a validated reversed-phase high-performance liquid chromatography (HPLC) system with fluorescence detection. Pharmacokinetic parameters, including peak concentration, area under the plasma concentration-time curve (AUC), clearance (CL), and the half-life of the terminal disposition phase were calculated. In the fasted group, plasma levels of SN-38 in the 50 mg/kg and 100 mg/kg group showed a 57% and 53% reduction, respectively, compared with ad libitum fed controls (AUC0-inf 5,149 vs. 2,242 ng*h/mL and 7,507 vs. 3,562 ng*h/mL). For CPT-11 the effects of fasting were smaller. An increase of 26% in the 50 mg/kg group and a reduction of 15% in the 100 mg/kg group were observed (AUC0-inf 9,715 vs. 12,235 and 37,360 vs. 31,924 ng*h/mL). In the liver, SN-38 levels in the 50 mg/kg and 100 mg/kg group showed a reduction of 51% and 30%, respectively, in the fasted animals (AUC0-inf 85.4 vs. 41.5 µg*h/g and 126 vs. 87.6 µg*h/g), while CPT-11 levels were reduced with 19% in the 50 mg/kg group and 28% in the 100 mg/kg group (AUC0-inf 218 vs. 177 µg*h/g and 712 vs. 512 µg*h/mg). Our data demonstrate that 72 hours of fasting prior to irinotecan administration induces an important change in its metabolism. Plasma and liver levels of the pro-drug CPT-11 were only slightly reduced in fasted animals. Levels of the active metabolite SN-38 were considerably lower in fasted animals compared to ad libitum fed animals. These data suggest that the reduction of side effects by fasting is due to the lower systemic exposure to SN-38, and may have important clinical implications if also found in humans. Citation Format: Sander A. Huisman, P de Bruijn, I.M. Ghobadi Moghaddam-Helmantel, J.N.M. IJzermans, E Wiemer, A.H.J. Mathijssen, R.W.F. de Bruin. Fasting reduces the systemic exposure to irinotecan and its active metabolite SN-38. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4627. doi:10.1158/1538-7445.AM2014-4627