DISPOSITION OF ENALAPRIL IN THE PERFUSED RAT INTESTINE-LIVER PREPARATION - ABSORPTION, METABOLISM AND 1ST-PASS EFFECT

  • 1 January 1985
    • journal article
    • research article
    • Vol. 233  (3) , 788-795
Abstract
An in situ perfused rat intestine-liver preparation was introduced to examine the roles of the intestine and the liver in the elimination of enalapril, an 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 reservior, 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. 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 .mu.M) used. Portal venous plasma consisted mainly of enalapril, and was devoid of enalaprilat; 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 .mu.mol) was made close to the pyloric sphinctor, whereas the intestine preparation was recirculated (7.5 ml/min) with blank perfusate. At the end of 3 h, [14C]enalaprilat was present in both luminal fluids and in perfusate, but the fraction as [14C]enalaprilat in luminal fluids was higher. The composite data for these 2 preparations suggest that [14C]enalaprilat in perfusate plasma resulted because of metabolism by gut bacteria or by intestinal enzymes which were not easily accessible to substrate in the circulation, and not through biotransformation of [14C]enalapril during its transit in intestinal tissue. The reasons were: the lack of [14C]enalaprilat in portal venous plasma in the single-pass intestinal-liver preparation, and the higher fraction of [14C]enalaprilat in the luminal fluid in the intestinal preparation. Taking the stand that [14C]enalaprilat in perfusate was due to absorption of [14C]enalaprilat formed in lumen, the rates and extents of absorption of [14C]enalapril were estimated by the amount remaining to be absorbed plot. The 1st order rate constant for enalapril absorption was 0.02 .+-. 0.008 min-1 and the extent of absorption in 3 h was 13.7 .+-. 2.2% dose.