STUDIES ON THE FIRST-PASS METABOLISM OF EBASTINE IN RATS

The metabolic conversion of ebastine (CAS 90729-43-4, LAS-90), an anti allergic agent, to its active principle carebastine (GAS 90729-42-3) i n the rat intestine and liver was investigated using intravenous-intra portal infusion techniques and jejunum loop preparations. The steady s tate blood concentrations of ebastine and carebastine were determined during continuous intravenous or intraportal infusion of ebastine to e valuate their respective activity to metabolize ebastine in the intest ine and liver. Total body clearance of ebastine was calculated to be a pproximately 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 concentrat ions of carebastine in portal blood to that in arterial blood was 1.41 during intravenous infusion, suggesting the single-pass metabolic con version of ebastine to carebastine in the intestine. The ratio of the arterial blood concentration of carebastine during intraportal infusio n to that during intravenous infusion was 1.88, suggesting the single- pass metabolic conversion in the liver. The contribution of the intest ine to form carebastine from ebastine present in the systemic circulat ion was thus about 1/2 (0.41/0.88) of that of the liver under these co nditions. When [C-14]ebastine was administered in the jejunal loop, ca rebastine was detected in the mesenteric plasma circulated from the lo op, as the major component accounting for approximately 56% of the pla sma radioactivity, while the unchanged ebastine was only about 13%. Th erefore, the jejunal tissue converted >1/2 of the permeated fraction o f ebastine to carebastine under these conditions. The results in the i nfusion 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 syst emic circulation firstly permeated the mucosa of small intestine and t hen 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.