No abstract

Carvedilol (CAS 72956-09-3, Dilatrend) is a beta-blocker with additional vasodilating, antiproliferative and antioxidative properties. It is indicated for the treatment of high tension (HT), coronary artery disease (CAD) and congestive heart failure (CHF). Carvedilol has been investigated in numerous in vivo studies and thus comparisons of in vitro results to in vivo observations are possible. In this publication the results of studies on the in vitro absorption of carvedilol in a new model called BM-RIMO (Boehringer-Mannheim ring model) using porcine intestine are reported. In particular the influence of absorption enhancers and of pH and the existence of absorption windows were examined and the relevance of the obtained data for in vivo conditions was estimated. The main route of carvedilol absorption seemed to be transcellular. In vitro as well as in vivo absorption decreased within the intestine in the following order: jejunum > ileum > colon. The highest amount of in vitro absorption of carvedilol was achieved in the jejunum at a neutral pH. Enhancers such as bile and the mucoadhesive agent chitosan had opposite effects on the absorption of the compound. The results indicate that BM-RIMO is a simple, cheap and fast tool for the investigation of the influence of absorption enhancers, pH and different parts of intestine on absorption. For carvedilol the in vitro model tends to overestimate absorption in the colon, possibly because of the lack of faeces.

Two compounds, an aminobisphosphonate (A) and a steroid (B), showing a very large difference in lipophilicity (log PC (A) = O, log PC (B) > 8) but both revealing very poorly absorption in vivo of less than 1% were tested in respect of in vitro absorption and mucoadhesion using a model with porcine intestine named RIMO (ring model). Explanations for the poor absorption of the two compounds were investigated in order to propose methods for absorption enhancement. Moreover, absorption and mucoadhesion were measured for different parts of intestine with radiolabelled substances. Last but not least the inhibiting effect of calcium ions was investigated as well as enhancement by DTT (dithiothreitol), EDTA and bile. Results showed that mucus plays an important role in oral bioavailability. The aminobisphosphonate formed a complex with calcium ions which was insoluble in the mucus and resulted in a smaller amount of substance being absorbed. The very lipophilic steroid was kept back from the mucosa by the hydrophilic mucus, but addition of the solubilizer bile increased the absorption. The results were in good agreement with in vivo bioavailability data. Therefore, simplicity of the model and easy access of porcine intestine by slaughter houses make RIMO a valuable tool for investigations concerning the role of mucus and influences of diverse additives on absorption.