In vitro activation of irinotecan to SN-38 by human liver and intestine

Background: Irinotecan (CPT-11) is hydrolyzed fly carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and he patic activation Materials and Methods: Irinotecan was incubated with S9 fi actions of human liver and intestinal tissues and the specific activity wa s determined based on the formation rate of SN-38. Results: Irinotecan was hydrolyzed to SN-38 by hepatic and intestinal S9 fractions with mean (+/-SD ) specific activities (pmoles/min/mg) of liver (8.57 +/- 10.4, n=8), duoden um (5.06 +/- 3.7, n=4), jejunum (6.44 +/- 2.8 n=5) ileum (4.81 +/- 2.4 n=5) , colon (1.93 +/- 1.5, n=6) and rectum (0.82, n=1). When incubated with S9 fractions obtained from tumor tissues, there appeared to be a decrease in S N-38 formation compared to matched normal liver and colon tissues. Conclusi on: Irinotecan undergoes conversion to ifs active metabolite in human intes tinal S9 fr actions and there is variability in the extent of SN-38 formati on. The localized intestinal activation of irinotecan to SN-38 may provide a rationale for the development of oral irinotecan for gastrointestinal mal ignancies but could also cause mucosal damage leading to toxicity.