Eicosanoid-mediated Cl^- secretion induced by the antitumor drug, irinotecan (CPT-11), in the rat colon

Irinotecan (CPT-11) is active against a broad range of human cancer. One of the side-effects of irinotecan is a strong diarrhoea. In order to investigate the mechanism underlying this diarrhoea, the effect of irinotecan on anion secretion across the isolated rat distal colon was studied. Irinotecan caused a concentration-dependent increase in short-circuit current (Isc). The increase in Isc was completely dependent on the presence of Cl^- ions and was supressed by furosemide and the Cl^- channel blocker NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), indicating that it is caused by a Cl^- secretion. The secretory response was inhibited by indomethacin, 1-benzylimidazole, a thromboxane synthase inhibitor, and SK&F 88046 ((N,N′bis-[7-(3-Chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydroisoquinolyl)disulfonylimide), a thromboxane A₂ receptor blocker. In isolated crypts irinotecan had no effect on the membrane potential. Consequently, the secretion induced by irinotecan is an indirect one, caused by the stimulation of eicosanoid production, e.g. thromboxane A₂, in the subepithelial tissue.