Inhibition of thromboxane A(2)-induced Cl- secretion by antidiarrhea drug loperamide in isolated rat colon

The antitumor drug irinotecan clinically causes severe diarrhea as a side e ffect. Thromboxane A(2) (TXA(2)), released by irinotecan, has been shown to be a novel physiological stimulant of Cl- secretion in the rat colon. Here in, we examined the effect of loperamide, an antidiarrhea drug, on Cl- secr etion induced by irinotecan; 9,11-epithio-11,12-methano-thromboxane A(2) (S TA(2)), a stable TXA(2) analog; and prostaglandin E-2 (PGE(2))by using isol ated mucosae of the rat colon. In the presence of atropine, loperamide in a concentration-dependent manner inhibited the Cl- secretion induced by irin otecan, STA(2), and PGE(2). However, the drug inhibited more effectively th e irinotecan- and STA(2)-induced secretion (IC50 = 0.7 and 1.2 mu M, respec tively) than the PGE(2)-induced secretion (IC50 = 23 mu M). Naloxone, an op iate antagonist, did not affect the antisecretory action of loperamide. Sim ilar to the case for loperamide, W-7, a specific calmodulin antagonist, inh ibited more effectively the STA(2-)induced Cl- secretion (IC50 = 5 mu M) th an the PGE(2)-induced secretion (IC50 = 36 mu M). W-5, a low-affinity calmo dulin antagonist (a dechlorinated control analog of W-7), also inhibited th e STA(2)-induced secretion, but this effect was much less than that of W-7. STA(2)-induced increase in the intracellular free Ca2+ concentration of si ngle colonic crypt cells was not affected by loperamide. We suggest that lo peramide efficiently inhibits the TXA(2)-induced secretion by blocking the calmodulin system in the colonic epithelium. The present results may explai n why coadministration of loperamide with irinotecan is clinically efficien t for avoiding the irinotecan- induced side effect of diarrhea.