ROLE OF INTESTINAL TRANSPORT AND FIRST PASS LIVER EXTRACTION ON ORAL DELIVERY OF RENIN INHIBITOR COMPOUNDS

The absolute bioavailabilities of three renin inhibitor compounds, one uncharged (compound I) and two positively charged (compounds II and I II), were found to be comparable (1-3%). To determine the role of inte stinal transport and first pass liver extraction (FPLE) in the oral de livery of these compounds intravenous, intraportal, intraduodenal and intraperitoneal studies were performed in the rat. In the intraduodena l studies, drug solutions were injected into the duodenum of anestheti zed rats and portal and systemic blood was collected. In the intraport al studies, the drug solutions were injected into the portal vein and systemic blood was collected. From the ratio of the area under the dru g concentration-time curves (tAUC) for the oral and intraportal studie s, 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 mu g/ml, respectively. The tAUC of compound I in portal. plasm a was 8-26-times higher than those for compounds II and III. From comp arison of the intraportal and intravenous tAUC values, the FPLE of com pounds I-III was estimated as 76 +/- 4, 61 +/- 3 and and +/- 23% (mean +/- SE), respectively. Overall, the results indicated that the intest inal transport and FPLE of compound I was the highest among the three analogs. Compound II showed low intestinal transport and high FPLE and compound In showed low intestinal transport and low but variable FPLE .