title: The in vitro metabolism of irinotecan (CPT-11) by carboxylesterase and beta-glucuronidase in human colorectal tumours.
abstract: OBJECTIVE
  Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation.
  
  
  METHODS
  The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients).
  
  
  RESULTS
  The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable.
  
  
  CONCLUSIONS
  Tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.
authors.affiliation: Department of Pharmacology, University of Sydney, and Department of Anatomical Pathology, Royal Prince Alfred Hospital, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Tobin
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.forename: J Paul
authors.initials: JP
authors.lastname: Seale
authors.forename: Soon
authors.initials: S
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Solomon
authors.forename: Sally
authors.initials: S
authors.lastname: Aulds
authors.forename: Michael
authors.initials: M
authors.lastname: Crawford
authors.forename: James
authors.initials: J
authors.lastname: Gallagher
authors.forename: Tony
authors.initials: T
authors.lastname: Eyers
authors.forename: Laurent
authors.initials: L
authors.lastname: Rivory
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D043182:Carboxylesterase / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D000077146:Irinotecan; D009596:Nitrophenols / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006912:Hydroxyquinolines; D009596:Nitrophenols; C056147:8-hydroxyquinoline glucuronide; D000077146:Irinotecan; D043182:Carboxylesterase; D005966:Glucuronidase; D002166:Camptothecin; C024836:4-nitrophenol