Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

This article is available online at http://dmd.aspetjournals.org

In this in vivo perfusion study verapamil increased the bioavailability of fexofenadine. Because the permeability, which is a direct measure of intestinal transport, was unchanged, we suggest that the major reason for this effect was decreased first-pass liver extraction of fexofenadine. The most plausible mechanism is either decreased organic anion transporting polypeptide-mediated sinusoidal uptake or P-glycoprotein-mediated canalicular secretion of fexofenadine, or both.

Aims  The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first‐pass metabolism of (R)‐ and (S)‐verapamil in humans. Methods  A regional single‐pass perfusion of the jejunum was performed using a Loc‐I‐Gut® perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)‐verapamil was 120 mg l−1 in both periods, and ketoconazole was added at 40 mg l−1 in period 2. (R/S)‐verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)‐ and (S)‐norverapamil were also estimated in the outlet jejunal perfusate. Results  The effective jejunal permeability (Peff) of both (R)‐ and (S)‐verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P‐glycoprotein mediated efflux. However, the appearance ratio of both (R)‐ and (S)‐norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)‐ and (S)‐verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)‐verapamil by ketoconazole. Conclusions  Ketoconazole did not affect the jejunal Peff of (R/S)‐verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P‐glycoprotein than of CYP3A4 in vivo in humans.

This study demonstrates the complex nature of the fluids available for drug dissolution in the stomach and the upper small intestine in humans. The results can be used when designing a more physiological in vitro dissolution media representative for the fasted state. When designing such a medium, we suggest that gender differences not be taken into account.