Studies on the first-pass metabolism of ebastine in rats

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 intravenous-intraportal infusion techniques and jejunum loop preparations. The steady state blood concentrations of ebastine and carebastine were determined during continuous intravenous or intraportal infusion of ebastine to evaluate their respective activity to metabolize ebastine in the intestine and liver. Total body clearance of ebastine was calculated to be approximately 22-26 ml/ min. The intestinal and hepatic clearances were 6.7 ml/min and 15.4 ml/min, respectively, accounting for about 32% and 60% of the total clearance, respectively. The ratio of the concentrations of carebastine in portal blood to that in arterial blood was 1.41 during intravenous infusion, suggesting the single-pass metabolic conversion of ebastine to carebastine in the intestine. The ratio of the arterial blood concentration of carebastine during intraportal infusion to that during intravenous 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 approximately 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.