Comparative pharmacokinetics of the histamine H1-receptor antagonist ebastine and its active metabolite carebastine in rats, guinea pigs, dogs and monkeys

Abstract

The pharmacokinetics of ebastine (CAS 90729-43-4), a new histamine H1-receptor antagonist, was investigated in rats, guinea pigs, dogs and monkeys. Plasma levels of ebastine and its active carboxylated metabolite, carebastine (CAS 90729-42-3), were determined after an intravenous dose (2 mg/kg) or an oral dose (10 mg/kg). After intravenous administration to dogs, plasma levels of the unchanged ebastine showed a bi-phasic decrease with a t1/2 alpha of 0.16 h and t1/2 beta of 4.2 h. In contrast, after oral administration, the unchanged ebastine was scarcely detected in plasma of 4 animal species examined, indicating extensive first-pass metabolism of ebastine. There were marked interspecies differences in the plasma concentration-time profiles of carebastine after oral administration of ebastine. The Cmax of carebastine in guinea pigs (2820 ng/ml) was markedly higher than that in rats (311 ng/ml), dogs (465 ng/ml) and monkeys (1036 ng/ml). Guinea pig also showed the slower elimination of carebastine (t1/2 of 9.4 h) than rat (0.92 h), dog (2.4 h) and monkey (1.2 h). After oral administration of carebastine to rats, the Cmax and AUC were approximately 3/4 of those after administration of ebastine. Once daily 7-day repeated oral administrations of ebastine did not affect the pharmacokinetics of ebastine and carebastine in rats. These findings strongly indicate that carebastine is responsible for the antihistamine activity after oral administration of ebastine.