Disposition of enalapril in the perfused rat intestine-liver preparation: absorption, metabolism and first-pass effect

Abstract

A new procedure, namely the in situ perfused rat intestine-liver preparation, was introduced to examine the roles of the intestine and the liver in the elimination of enalapril, a new angiotensin-converting enzyme inhibitor. The in situ perfused rat intestine preparation was used to determine the rate and extent of enalapril absorption after an-intraduodenal dose. In the former technique, enalapril in blood perfusate (10 ml/min) was delivered via the superior mesenteric artery into the once-through perfused rat intestine-liver preparation, with sampling effected in reservoir, portal vein and hepatic vein. The ease of sampling, proximal and distal to the intestine and liver, allowed the direct estimation of the extraction ratios by the intestine and the liver. The steady-state intestinal extraction ratio of enalapril was small (0.04 +/- 0.066) compared to that for the liver (0.74 +/- 0.06), indicating that the liver was responsible for most of the hydrolytic conversion of enalapril to its pharmacologically active diacid metabolite, enalaprilat. Moreover, no trend in the values of the extraction ratios by both organs was apparent among the input concentrations of enalapril (0.55, 2.6 and 13.3 microM) used. Portal venous plasma consisted mainly of enalapril and was devoid of enalaprilat, whereas both enalapril and enalaprilat were detected in bile and hepatic venous plasma. With the latter technique, an intraduodenal injection of a tracer dose of [14C]enalapril (0.14-0.39 mumol) was made close to the pyloric sphinctor, whereas the intestine preparation was recirculated (7.5 ml/min) with blank perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)