Reference

Studies on the first-pass metabolism of ebastine in rats

Studies on the first-pass metabolism of ebastine in rats. Fujii, Toshihiko; Matsumoto, Satoshi; Hatoyama, Teruo; Miyazaki, Hisashi (Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita 564, Japan). Arzneimittel-Forschung, 47(8), 949-953 (English) 1997 Cantor. CODEN: ARZNAD. ISSN: 0004-4172. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The metabolic conversion of ebastine (CAS 90729-43-4, LAS-90), an antiallergic agent, to its active principle carebastine (CAS 90729-42-3) in the rat intestine and liver was investigated using i.v.-intraportal infusion techniques and jejunum loop prepns. The steady state blood concns. of ebastine and carebastine were detd. during continuous i.v. or intraportal infusion of ebastine to evaluate their resp. activity to metabolize ebastine in the intestine and liver. Total body clearance of ebastine was calcd. to be approx. 22-26 mL/ min. The intestinal and hepatic clearances were 6.7 mL/min and 15.4 mL/min, resp., accounting for about 32% and 60% of the total clearance, resp. The ratio of the concns. of carebastine in portal blood to that in arterial blood was 1.41 during i.v. infusion, suggesting the single-pass metabolic conversion of ebastine to carebastine in the intestine. The ratio of the arterial blood concn. of carebastine during intraportal infusion to that during i.v. infusion was 1.88, suggesting the single-pass metabolic conversion in the liver. The contribution of the intestine to form carebastine from ebastine present in the systemic circulation was thus about 1/2 (0.41/0.88) of that of the liver under these conditions. When [14C]ebastine was administered in the jejunal loop, carebastine was detected in the mesenteric plasma circulated from the loop, as the major component accounting for approx. 56% of the plasma radioactivity, while the unchanged ebastine was only about 13%. Therefore, the jejunal tissue converted > 1/2 of the permeated fraction of ebastine to carebastine under these conditions. The results in the infusion studies suggested that metabolic potential to convert ebastine to carebastine was higher in the liver than in the intestine. However, since after oral administration all of the drug appeared in the systemic circulation firstly permeated the mucosa of small intestine and then passed through the liver, the contribution of the small intestine in the metabolic conversion of ebastine given orally would be greater than that of the liver, as suggested by the above in situ jejunum loop study.

Comparative antiallergic effects of second-generation H1-antihistamines ebastine, cetirizine and loratadine in preclinical models

Comparative antiallergic effects of second-generation H1-antihistamines ebastine, cetirizine and loratadine in preclinical models. Llupia, Josep; Gras, Jordi; Llenas, Jesus (Research Center, Almirall Prodesfarma, Barcelona, Spain). Arzneimittel-Forschung, 53(2), 93-97 (English) 2003 Editio Cantor Verlag. CODEN: ARZNAD. ISSN: 0004-4172. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Ebastine (CAS 90729-43-4), cetirizine (CAS 83881-51-0) and loratadine (CAS 79794-75-5) are second generation H1-antihistamines of proven efficacy for treating allergy. Recent clin. studies have found ebastine to be more effective than cetirizine or loratadine in alleviating the symptoms of seasonal allergic rhinitis. The objective of this study was to compare the efficacy of these compds. in three guinea-pig models of bronchoconstriction, elicited either by histamine, allergen or leukotriene C4 in order to shed light onto the mechanisms that might explain differences found in clin. studies. In the present expts., ebastine and cetirizine were equipotent against aerosol histamine-induced bronchospasm in guinea pigs (ED50 115 and 100 mg/kg p.o., resp.), while loratadine was three-fold less potent. In the same model the effects of ebastine, loratadine and cetirizine lasted 21, 19 and 15 h, resp. Ebastine (ED50 334 mg/kg p.o.) was the most potent compd. in inhibiting allergen-induced bronchospasm in conscious guinea pigs. In vitro studies in tracheally perfused guinea pig lungs demonstrated that ebastine and loratadine inhibited with equal potency the bronchoconstriction induced by leukotriene C4 while cetirizine was significantly less potent. Finally, in another in vivo study, ebastine reverted the changes in pulmonary resistance induced by leukotriene C4 in anesthetized guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. In accordance with the clin. data, ebastine proved to be the substance with the widest range of application in animal expts., too.