Altered irinotecan pharmacokinetics in diet‐induced obesity (1052.6)

Abstract

Irinotecan (CPT‐11) is a topoisomerase I inhibitor which is highly effective in treatment of variety of cancers. It was found that patients with a BMI>25 were twice as much susceptible to developing irinotecan‐induced liver toxicity than patients with BMI<25. CPT‐11 is metabolized to SN‐38, which then undergoes glucuronidation by uridine glucuronosyl transferase (Ugt)1a1 to form SN‐38 glucuronide (SN‐38G). Excess accumulation of the toxic metabolite SN‐38 is known to cause fatal diarrhea in cancer patients. We hypothesize that reduction in Ugt1a1‐mediated SN‐38 glucuronidation causes SN‐38 accumulation leading to liver toxicity in obesity. Metabolism studies in liver S9 fractions showed that the rate of formation of SN‐38G was 2‐fold lower in the diet‐induced obese (DIO) mice compared to the lean controls. Pharmacokinetic studies showed plasma exposure of SN‐38 increased while that of SN‐38G decreased by 2‐folds in the DIO mice as compared to the lean controls. This corresponded with reduced expression of Ugt1a1 in DIO mice livers. We also observed significantly higher mRNA and serum levels of TNFα in the DIO mice as compared to the lean mice. Higher TNFα levels are known to be associated with liver toxicity. Thus, CPT‐11 dosage should be closely monitored for effective and safe chemotherapy in obese patients who are at a higher risk of developing liver toxicity.