Impact of obesity on accumulation of the toxic irinotecan metabolite, SN-38, in mice

Aim: Our aim is to investigate the impact of high fat diet-induced obesity on plasma concentrations of the toxic irinotecan metabolite, SN-38, in mice. Main methods: Diet-induced obese (DID, 60% kcal fed) and lean mice (10% kcal fed) were treated orally with a single dose of 10 mg/kg irinotecan to determine pharmacokinetic (PR) parameters. Feces and livers were collected for quantification of irinotecan and its metabolites (SN-38 82SN-38G). SN-38G formation by Ugtl al enzyme was analyzed in liver S9 fractions. Expression of the pro-inflammatory cytokine, TNF-alpha was determined in liver and plasma. Hepatic beta-glucuronidase and carboxylesterase enzymes (CES) were also determined. Key findings: AUC(0 - 8) and C-max. of SN-38 increased by 2-fold in DID mice compared to their lean controls. This was accompanied by a similar to 2-fold reduction in AUC(0-8) and C-max of SN-38G in DID mice. There were no differences in the PR parameters of irinotecan in DID or lean mice. Conversion of SN-38 to SN-38G by Ugtlal enzyme was reduced by similar to 2-fold in liver S9 fractions in DID mice. Furthermore, in DID mice, beta-glucuronidase activity increased by 2-fold, whereas there was no change in CES activity. TNF-alpha mRNA expression was 3 fold higher in DID mice. Significance: Our study demonstrates that reduced hepatic Ugtl a activity during obesity likely contributes to reduced glucuronidation, and results in higher levels of the toxic metabolite, SN-38. Thus, irinotecan dosage should be closely monitored for effective and safe chemotherapy in obese cancer patients who are at a higher risk of developing liver toxicity. (C) 2015 Elsevier Inc. All rights reserved.