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标题：Comparison of the Antidiarrheal Effects of Zaldaride Maleate and Its Optical Isomers in Rats
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作者：Nobuo AIKAWA ; Kaori HORIKOSHI ; Hiroshi MAEDA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2000
卷号：23
期号：4
页码：402-405
DOI：10.1248/bpb.23.402
出版社：The Pharmaceutical Society of Japan
摘要：Zaldaride maleate (ZAL), a calmodulin inhibitor, that ameliorates secretory diarrhea in rodents, has a racemic structure. In this study, we compared the antidiarrheal and antisecretory effects of ZAL and its optical isomers, R(-)-isomer and S(+)-simer, in rats. In Ussing chamber experiments, the inhibitory action of ZAL on acetylcholine-induced ion transport in the rat colonic mucosa was equipotent for both optical isomers, with IC₅₀ values of apprpximately 3-4 μmol/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 E₂-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 administration of 30 mg/kg (p.o.) of each compound were as follows : ZAL (C_max : 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/ml) (mean, N=4). In conclusion, despite the fact that the antisecretory actions of ZAL and its optical isomers are the same, the antidiarrheal actions 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.
关键词：zaldaride maleate;diarrhea;castor oil;prostaglandin E2;calmodulin;optical isomer