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

Anticancer Res. May-Jun 1999;19(3A):2067-71.

Abstract

Background: Irinotecan (CPT-11) is hydrolyzed by carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and hepatic activation. MATERNALS 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.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Biotransformation
  • Camptothecin / analogs & derivatives*
  • Camptothecin / biosynthesis
  • Camptothecin / pharmacokinetics
  • Carboxylic Ester Hydrolases / metabolism
  • Colon / metabolism
  • Duodenum / metabolism
  • Humans
  • Hydrolysis
  • Ileum / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestinal Neoplasms / metabolism*
  • Irinotecan
  • Jejunum / metabolism
  • Liver Neoplasms / metabolism*
  • Microsomes / metabolism
  • Microsomes, Liver / metabolism*
  • Neoplasm Proteins / metabolism
  • Organ Specificity
  • Prodrugs / pharmacokinetics*
  • Rectum / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Neoplasm Proteins
  • Prodrugs
  • Irinotecan
  • Carboxylic Ester Hydrolases
  • Camptothecin