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The in vitro metabolism of irinotecan (CPT‐11) by carboxylesterase and β‐glucuronidase in human colorectal tumours
Author(s) -
Tobin Peter,
Clarke Stephen,
Seale J Paul,
Lee Soon,
Solomon Michael,
Aulds Sally,
Crawford Michael,
Gallagher James,
Eyers Tony,
Rivory Laurent
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02477.x
Subject(s) - glucuronide , irinotecan , sn 38 , carboxylesterase , glucuronidation , glucuronidase , chemistry , topoisomerase , metabolism , in vivo , glucuronosyltransferase , in vitro , medicine , colorectal cancer , enzyme , endocrinology , pharmacology , biology , biochemistry , cancer , microsome , microbiology and biotechnology
Aims 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 β‐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 µ m ) 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 µ m ) 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 β‐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 µ m SN‐38 glucuronide; P > 0.05). β‐Glucuronidase activity in tumour correlated to that observed in matched normal tissue ( r 2 > 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 β‐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 β‐glucuronidase may play a significant role in the exposure of tumours to SN‐38 in vivo .