gms | German Medical Science

Oral drug absorption is a very complex process and is influenced by many factors as the characteristics of the administered dosage form, intestinal motility, the availability of water for dissolution, and, notably, the function of intestinal drug transporters and drug-metabolizing enzymes in the enterocytes, predominantly in the jejunum and ileum. Therefore, bioavailability cannot be predicted by a simple static model, which compares the intestine to a water-filled tube with identical drug permeability along its entire length. In this model, a concentration gradient drives drug permeability, and prediction of that gradient is calculated using the ratio of the oral dose to the water volume recommended for swallowing. However, the physiologic background for drug absorption is clearly much more complicated. First, our MR-imaging studies in fasting healthy subjects demonstrated that water for administration of dosage forms is rapidly absorbed and that, thereafter, the freely accessible water along the entire small intestine is small and scattered in a few pockets. Fast water absorption after gastric emptying may concentrate immediate-release drugs and facilitate their intestinal absorption. Second, drug transporters and drug-metabolizing enzymes are not homogenously expressed along the gastrointestinal tract. Site-dependent differences in the longitudinal protein abundance of intestinal enzymes and transporters are likely a reason for the substantial differences in drug absorption along the human intestine that have been observed after administration of different dosage forms, after bariatric surgery, or in intestinal perfusion studies. In most cases, protein content of transporters and metabolizing enzymes is not predicted by mRNA-expression which, however, is highly correlated to the respective nuclear sensors (e.g. CAR, PXR). Additional mechanisms to control protein abundance along the gut must be discussed. Third, gastrointestinal motility and methods to measure it must be considered in clinical studies on drug absorption. Finally, food or intake of caloric fluids may substantially change the physiological background for drug absorption. In the light of that physiological background, „permeability” of drugs in their respective dosage forms must be characterized by using valid models to measure affinity of drugs to metabolizing enzymes and drug transporters in-vitro and by using physiological-based in-vitro („stress”) models to predict in-vivo liberation of dosage forms.