Absorption, distribution, metabolism and excretion of [14C]ebastine after repeated oral administration in rats

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a new potent histamine H1-receptor antagonist, were studied with 14C-labeled compound in male rats during and after 21 consecutive daily oral 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 administration were lower than the reliable limit of radioactivity measurements during the course of the experiment. Plasma level reached the maximum (Cmax) of 109 ng eq./ml at 2 h after the 21st administration and decreased monophasically with a half-life (t1/2) of 2.5 h, which was similar to the results in the previous single dose study. [14C]Ebastine radioactivity was distributed to the liver, kidney, submaxillary gland, hypophysis, adrenal, lung and pancreas twice as high or more, and to others including brain similarly as or lower than in plasma, at 1 h after the last administration. At 168 h, radioactivity was detected at low 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, within 24 h after each administration and radioactivity was virtually completely excreted within 120 h after the last administration. The analysis by thin-layer chromatography revealed that the composition of radioactive metabolites in plasma, urine and feces after repeated administration was similar to that in the single dose study.(ABSTRACT TRUNCATED AT 250 WORDS)