TY - JOUR T1 - Inhibition of Thromboxane A<sub>2</sub>-Induced Cl<sup>−</sup>Secretion by Antidiarrhea Drug Loperamide in Isolated Rat Colon JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 233 LP - 238 VL - 295 IS - 1 AU - Tomoyuki Suzuki AU - Hideki Sakai AU - Akira Ikari AU - Noriaki Takeguchi Y1 - 2000/10/01 UR - http://jpet.aspetjournals.org/content/295/1/233.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -