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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our study demonstrates that reduced hepatic Ugt1a 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.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
Pankajini
P
Mallick
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, USA.
Pranav
P
Shah
Department of Bioanalysis and Physiology, Lundbeck Research Inc. USA, Paramus, NJ, USA.
Adarsh
A
Gandhi
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. Electronic address: rghose@uh.edu.
Romi
R
Ghose
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D043182:Carboxylesterase / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005243:Feces / Q000737:chemistry; D005965:Glucuronates / Q000378:metabolism* / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D043182:Carboxylesterase; D005965:Glucuronates; D005966:Glucuronidase; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide
Chemotherapy; Colorectal cancer; Irinotecan; Obesity; Pharmacokinetics; SN-38; Ugt1a1