The in vitro metabolism of irinotecan (CPT-11) by carboxylesterase and beta-glucuronidase in human colorectal tumours.
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.
Tobin
Peter
P
Department of Pharmacology, University of Sydney, and Department of Anatomical Pathology, Royal Prince Alfred Hospital, New South Wales, Australia.
Clarke
Stephen
S
Seale
J Paul
JP
Lee
Soon
S
Solomon
Michael
M
Aulds
Sally
S
Crawford
Michael
M
Gallagher
James
J
Eyers
Tony
T
Rivory
Laurent
L
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
D000972:Antineoplastic Agents, Phytogenic; D006912:Hydroxyquinolines; D009596:Nitrophenols; C056147:8-hydroxyquinoline glucuronide; D000077146:Irinotecan; D043182:Carboxylesterase; D005966:Glucuronidase; D002166:Camptothecin; C024836:4-nitrophenol