IMPORTANCE OF METABOLIC STABILITY AND HEPATIC DISTRIBUTION TO THE PHARMACOKINETIC PROFILE OF AMLODIPINE

1. In an isolated perfused rat liver (IPRL) model, the extensive hepat ic uptake and subsequent slow redistribution of amlodipine into the pe rfusate have been demonstrated. The apparent liver volume for amlodipi ne was 920 ml compared with 38 ml for nitrendipine. 2. Metabolism is t he major clearance mechanism of amlodipine and nitrendipine in animals and man. In the IPRL, the intrinsic (metabolic) clearance and first-p ass extraction values for amlodipine are similar to those of nitrendip ine. This is in contrast with in vitro metabolic stability data in rat liver microsomes which indicate about 40-fold greater metabolic stabi lity for amlodipine. 3. The discrepancy between relative clearance rat es for the two preparations may be explained by consideration of the h epatic volume of the two compounds, with the higher liver volume of am lodipine amplifying the whole organ clearance.