ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION OF [C-14] EBASTINEAFTER REPEATED ORAL-ADMINISTRATION IN RATS

Absorption, distribution, metabolism and excretion of ebastine yl-4-[4 -(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a new potent histamine H-1-receptor antagonist, were studied with C-14- labeled compound in male rats during and after 21 consecutive daily or al administrations at a dose of 2 mg/kg/d. Plasma levels at 2 h after each administration were virtually constant in the range of 81-166 ng eq./ml for 21 days. The plasma levels at 24 h following each administr ation were lower than the reliable limit of radioactivity measurement during the course of the experiment. Plasma level reached the maximum (C-max) of 109 ng eq./ml at 2 h after the 21st administration and decr eased monophasically with a half-life (t(1/2)) of 2.5 h, which was sim ilar to the results in the previous single dose study. [C-14]Ebastine radioactivity was distributed to the liver kidney submaxillary gland h ypophysis, adrenal, lung and pancreas twice as high or more, and to ot hers including brain similarly, as or lower than in plasma, at 1 h aft er the last administration. At 168 h, radioactivity was detected at lo w levels in several tissues such as liver, kidney, submaxillary gland etc. and not in other examined tissues. About 2-3 % and more than 90 % of the daily dose were excreted in urine and feces, respectively, wit hin 24 h after each administration and radioactivity was virtually com pletely excreted within 120 h after the last administration. The analy sis by thin-layer chromatography revealed that the composition of radi oactive metabolites in plasma, urine and feces after repeated administ ration was similar to that in the single dose study. In the plasma 1 h after the last administration, carebastine, an active carboxylic acid derivative was the major metabolite, and unchanged ebastine was hardl y detected. In urine pooled over 24 h following the last dose, polar m etabolite(s) were observed as major one(s), and ebastine and carebasti ne were virtually undetectable. In 24-h feces, ebastine, carebustine, and four other metabolites were observed.