Abstract

The antitumor drug irinotecan clinically causes severe diarrhea as a side effect. Thromboxane A₂ (TXA₂), released by irinotecan, has been shown to be a novel physiological stimulant of Cl⁻ secretion in the rat colon. Herein, we examined the effect of loperamide, an antidiarrhea drug, on Cl⁻secretion induced by irinotecan; 9,11-epithio-11,12-methano-thromboxane A₂(STA₂), a stable TXA₂ analog; and prostaglandin E₂ (PGE₂) by using isolated mucosae of the rat colon. In the presence of atropine, loperamide in a concentration-dependent manner inhibited the Cl⁻ secretion induced by irinotecan, STA₂, and PGE₂. However, the drug inhibited more effectively the irinotecan- and STA₂-induced secretion (IC₅₀ = 0.7 and 1.2 μM, respectively) than the PGE₂-induced secretion (IC₅₀ = 23 μM). Naloxone, an opiate antagonist, did not affect the antisecretory action of loperamide. Similar to the case for loperamide, W-7, a specific calmodulin antagonist, inhibited more effectively the STA₂-induced Cl⁻ secretion (IC₅₀ = 5 μM) than the PGE₂-induced secretion (IC₅₀ = 36 μM). W-5, a low-affinity calmodulin antagonist (a dechlorinated control analog of W-7), also inhibited the STA₂-induced secretion, but this effect was much less than that of W-7. STA₂-induced increase in the intracellular free Ca²⁺ concentration of single colonic crypt cells was not affected by loperamide. We suggest that loperamide efficiently inhibits the TXA₂-induced secretion by blocking the calmodulin system in the colonic epithelium. The present results may explain why coadministration of loperamide with irinotecan is clinically efficient for avoiding the irinotecan-induced side effect of diarrhea.