Altered Irinotecan Pharmacokinetics During Inflammation in Mice

Abstract

Irinotecan is an anti‐cancer drugprimarily used in the treatment of colorectal cancer and its primary metabolite, SN‐38, is an active compound that also causes intestinal toxicity. It is widelyknown that inflammation downregulates the expression of many drug metabolizingenzymes, resulting in changes in drug disposition. Our aim is to investigate the role of inflammation on pharmacokinetics of irinotecan and its metabolites, SN‐38 and SN‐38G. Mice (C57BL6, male) were treated with either saline or LPS(2mg/kg) I.P and Irinotecan (10 mg/kg) was administered 16 hours later via oralgavage. Blood samples were collected by snipping the tail at different time points from 0–24 h and the blood concentrations of CPT‐11, SN‐38, and SN‐38G were measured by LC‐MS/MS. The concentrations of SN‐38 were found to be significantly higher in LPS treatment group compared to saline group. Our findings show that the toxic metabolite SN‐38 blood concentrations were increased during inflammation, which suggests that patients with inflammation may have higher risk of adverse effects of irinotecan due to higher SN‐38 concentrations.