A Pharmacokinetic Study of Irinotecan (CPT‐11) During Inflammation in Mice

Purpose Irinotecan is a potent and widely used anticancer drug for the treatment of metastatic colorectal cancer and elevated concentrations of its active metabolite, SN‐38, causes severe diarrhea, which is a dose‐limiting toxicity of Irinotecan. It has been previously reported that inflammation downregulates the expression and activity of UGT1A1 and carboxylesterase enzymes, which are involved in the metabolism of Irinotecan to SN‐38. However, the role of inflammation in the disposition of Irinotecan has never been studied. Therefore, the aim of this study was to investigate whether the pharmacokinetics of Irinotecan is altered during inflammation and to develop a model to predict Irinotecan and its metabolite pharmacokinetics. Methods Pharmacokinetic Study Male C57BL6 mice of 7–8 weeks age were injected either saline or LPS (2 mg/kg) via I.P route and Irinotecan (10 mg/kg) was administered via oral gavage after 1 or 16 h of LPS injection. After Irinotecan was given, blood samples were collected from 0–24 h at different time points from the tail vein and the samples were analyzed for Irinotecan, SN‐38, and SN‐38 Glucuronide concentrations by UPLC‐MS/MS. Determination of Pharmacokinetic Parameters AUC, Cmax, and Tmax values for Irinotecan, SN‐38, and SN‐38G were calculated by using Phoenix WinNonlin 5.2 software. Pharmacokinetic Modeling A linear mechanistic model for Irinotecan, and a non‐linear entero‐hepatic recycling model for SN‐38 were developed to predict their pharmacokinetics during inflammation. A correlation between the observed and predicted concentrations of Irinotecan and SN‐38 pharmacokinetic data was obtained by individual fitting for each mouse in saline‐treated mice group. A population PK will be performed for a better prediction of the parent and metabolite concentrations during inflammation. Results The blood concentrations of both Irinotecan and its metabolites SN‐38, and SN‐38G were significantly higher in mice treated with LPS as compared to saline treated mice. A second peak in the pharmacokinetic profile of SN‐38 that correlated to enterohepatic recycling was observed exactly at the 2‐hour time point. The AUC and Cmax values of SN‐38 were approximately 7 and 5‐fold higher in LPS‐treated mice, respectively. Surprisingly, the AUC and Cmax of Irinotecan and SN‐38G metabolite concentrations were also significantly higher in LPS group mice, with approximately 4‐fold increase for Irinotecan and 3‐fold increase for SN‐38G. Conclusion Our study shows an important finding that the blood concentrations of the toxic SN‐38 metabolite were significantly higher in mice with inflammation. Moreover, the AUC of SN‐38 was 7‐fold higher in LPS‐treated mice. These results indicate that patients with inflammation are at a very high risk of experiencing gastrointestinal toxicity upon Irinotecan administration due to increased SN‐38 metabolite concentrations. Additionally, an enterohepatic recycling pharmacokinetic model was developed and a good correlation was obtained to predict Irinotecan and SN‐38 concentrations during inflammation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .