Simultaneous Prediction of Intestinal Absorption and Metabolism Using the Mini-Ussing Chamber System

The purpose of this study was to investigate the possibility of simultaneous prediction of the intestinal absorption and metabolism in a mini-Ussing chamber equipped with rat intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts, by mass balance method, transported to the basal-side component and drug amounts accumulated in the tissue, which are normalized by area under the curve of the drug in the apical compartment. Midazolam and nifedipine with high permeability were used as typical P450 substrates to examine the possibility of simultaneous prediction of intestinal absorption and metabolism. The metabolite formation of both compounds was observed and ketoconazole strongly inhibited the metabolite formation of both compounds in rat intestinal tissues, leading to the improvement of the TI value to a statistically significant extent for both compounds. TI ratio of nifedipine between in the presence and absence of ketoconazole was larger than that of midazolam, which was consistent with the reported lower value of fraction absorbed multiplied by intestinal availability of nifedipine. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to predict the intestinal absorption and metabolism simultaneously.