Comparison of the antidiarrheal effects of zaldaride maleate and its optical isomers in rats

Zaldaride maleate (ZAL), a calmodulin inhibitor, that ameliorates secretory diarrhea in rodents, has a racemic structure. In this study, we compared t he antidiarrheal and antisecretory effects of ZAL and its optical isomers, R(-)-isomer and S(+)-isomer, in rats. In Ussing chamber experiments, the in hibitory action of ZAL on acetylcholine-induced ion transport in the rat co lonic mucosa was equipotent for both optical isomers, with IC50 values of a pproximately 3-4 mu mol/l. In castor-oil-induced diarrhea, ZAL and its S(+) -isomer inhibited the incidence of diarrhea, whereas the R(-)-isomer had no effect, In 16,16-dimethyl prostaglandin E-2-induced diarrhea, ZAL, the S()-isomer and the R(-)-isomer significantly ameliorated diarrhea at doses of 30, 10 and 30 mg/kg (p.o.), respectively; the ED50 values were 25, 10 and above 30 mg/kg (p.o.), respectively. The pharmacokinetic parameters after a dministration of 30 mg/kg (p.o.) of each compound were as follows: ZAL (C-m ax: 378 ng/ml, AUC(0-12): 1650 ng-h/ml); S(+)-isomer (C-max: 565 ng/ml, AUC (0-12): 2230 ng-h/ml) and R(-)-isomer (C-max: 271 ng/ml, AUC(0-12): 613 ng- h/m) (mean, N=4). In conclusion, despite the fact that the antisecretory ac tions of ZAL and its optical isomers are the same, the antidiarrheal action s of ZAL and its S(+)-isomer are more potent than that of the R(-)-isomer, The antidiarrheal actions of ZAL and its optical isomers may be related to plasma levels.