The absolute bioavailabilities of three renin inhibitor compounds, one uncharged (compound I) and two positively charged (compounds II and III), were found to be comparable (1-3%). To determine the role of intestinal transport and first pass liver extraction (FPLE) in the oral delivery of these compounds intravenous, intraportal, intraduodenal and intraperitoneal studies were performed in the rat. In the intraduodenal studies, drug solutions were injected into the duodenum of anesthetized rats and portal and systemic blood was collected. In the intraportal studies, the drug solutions were injected into the portal vein and systemic blood was collected. From the ratio of the area under the drug concentration-time curves (tAUC) for the oral and intraportal studies, the extent of intestinal transport of compounds I-III was estimated as 9.7, 2.2 and 2.2%, respectively. In the intraduodenal studies the maximum portal plasma concentrations of compounds I-III were 2.8, 0.5 and 0.2 μg/ml, respectively. The tAUC of compound I in portal plasma was 8-26-times higher than those for compounds II and III. From comparison of the intraportal and intravenous tAUC values, the FPLE of compounds I-III was estimated as 76 ± 4, 61 ± 3 and 8 ± 23% (mean ± SE), respectively. Overall, the results indicated that the intestinal transport and FPLE of compound I was the highest among the three analogs. Compound II showed low intestinal transport and high FPLE and compound III showed low intestinal transport and low but variable FPLE. © 1994.
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