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

Life Sciences
Pankajini MallickRomi Ghose

Abstract

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. Diet-induced obese (DIO, 60% kcal fed) and lean mice (10% kcal fed) were treated orally with a single dose of 10mg/kg irinotecan to determine pharmacokinetic (PK) parameters. Feces and livers were collected for quantification of irinotecan and its metabolites (SN-38 & SN-38G). SN-38G formation by Ugt1a1 enzyme was analyzed in liver S9 fractions. Expression of the pro-inflammatory cytokine, TNF-α was determined in liver and plasma. Hepatic β-glucuronidase and carboxylesterase enzymes (CES) were also determined. AUC0-8 and Cmax of SN-38 increased by 2-fold in DIO mice compared to their lean controls. This was accompanied by a~2-fold reduction in AUC0-8 and Cmax of SN-38G in DIO mice. There were no differences in the PK parameters of irinotecan in DIO or lean mice. Conversion of SN-38 to SN-38G by Ugt1a1 enzyme was reduced by ~2-fold in liver S9 fractions in DIO mice. Furthermore, in DIO mice, β-glucuronidase activity increased by 2-fold, whereas there was no change in CES activity. TNF-α mRNA expression was 3 fold higher in DIO mice. Our study demonstrates that reduced hepatic Ugt1a ac...Continue Reading

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Citations

Aug 26, 2020·Expert Opinion on Drug Metabolism & Toxicology·Gabriel TaoRomi Ghose
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Yue SuiJianping Chen

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