Y. Kawato, M. Sekiguchi, K. Akahane
May 1, 1993
Citations
3
Influential Citations
49
Citations
Quality indicators
Journal
Journal of Pharmacy and Pharmacology
Abstract
Abstract— A camptothecin derivative, 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT‐11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine‐like action on the guinea‐pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT‐11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0·2 and 5 μm. These inhibitions were induced by camptothecin derivatives having an amino group at the C‐10 position (or the C‐4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU‐6596 and DU‐6888, two hexacyclic derivatives having the aminomethyl group at the C‐4 position, and of CPT‐11. DU‐6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT‐11, DU‐6596 and DU‐6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C‐10 position (or the C‐4 position) relates to the early defecation or diarrhoea and vomiting.