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Cholinergic toxic syndrome by the anticancer drug irinotecan: Acetylcholinesterase does not play a major role
Author(s) -
Blandizzi Corrado,
Danesi Romano,
De Paolis Barbara,
Di Paolo Antonello,
Colucci Rocchina,
Falcone Alfredo,
Del Tacca Mario
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.121909
Subject(s) - acetylcholinesterase , irinotecan , pharmacology , camptothecin , physostigmine , cholinergic , medicine , chemistry , cancer , enzyme , acetylcholine , colorectal cancer , biochemistry
Background The anticancer drug irinotecan induces cholinergic side effects that are currently ascribed to the blockade of acetylcholinesterase. This study investigated (1) the pattern of acetylcholinesterase activity in patients receiving treatment with irinotecan and (2) the relationship between acetylcholinesterase activity and plasma concentrations of irinotecan, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), and SN‐38 glucuronide (SN‐38G). Methods Twenty‐five patients with advanced colorectal cancer were treated with 250 mg/m 2 irinotecan administered by intravenous infusion for 60 minutes. Blood samples were collected before drug infusion and at 15 minutes and 45 minutes after the start of drug infusion. Blood acetylcholinesterase activity was determined by a colorimetric enzymatic assay, and irinotecan, SN‐38, and SN‐38G concentrations were determined in plasma by HPLC. The in vitro effects of irinotecan and other drugs on human acetylcholinesterase were also assessed. Results Compared with basal values, the activity of acetylcholinesterase in blood specimens collected during irinotecan infusion at 15 minutes (−0.76%) and at 45 minutes (−1.50%) showed no changes. No relationships were established between the activity of blood acetylcholinesterase at 15 or 45 minutes and plasma concentrations of irinotecan, SN‐38, or SN‐38G measured at the same time points. In vitro, the activity of acetylcholinesterase was inhibited by 100‐μmol/L irinotecan (−24.8%) and markedly reduced by 1‐μmol/L physostigmine (−86.7%), whereas neither SN‐38 nor camptothecin had an effect. Conclusions Although the use of erythrocyte acetylcholinesterase as a surrogate marker of acetylcholinesterase activity in the nervous system has not been firmly established, our findings do not support the hypothesis that the toxic cholinergic syndrome associated with irinotecan treatment depends on acetylcholinesterase blockade. Clinical Pharmacology & Therapeutics (2002) 71 , 263–271; doi: 10.1067/mcp.2002.121909