In vitro activation of irinotecan to SN-38 by human liver and intestine
Ahmed, F.; Vyas, V.; Cornfield, A.; Goodin, S.; Ravikumar, T.S.; Rubin, E.H.; Gupta, E.
Anticancer Research 19(3a): 2067-2071
1999
ISSN/ISBN: 0250-7005 PMID: 10470149 Document Number: 501195
Background: Irinotecan (CPT-11) is hydrolyzed by carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and hepatic activation. Matenals and Methods: Irinotecan was incubated with S9 fractions of human liver and intestinal tissues and the specific activity was 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), duodenum (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 SN-38 formation compared to matched normal liver and colon tissues. Conclusion: Irinotecan undergoes conversion to its active metabolite in human intestinal S9 fractions and there is variability in the extent of SN-38 formation. The localized intestinal activation of irinotecan to SN-38 may provide a rationale for the development of oral irinotecan for gastrointestinal malignancies but could also cause mucosal damage leading to toxicity.