DOES FLUID-FLOW ACROSS THE INTESTINAL-MUCOSA AFFECT QUANTITATIVE ORAL-DRUG ABSORPTION - IS IT TIME FOR A REEVALUATION

Purpose. Hydrophilic and charged solutes have a lower membrane permeab ility which is due to a lower partition into the lipid membrane (low s olubility in the membrane phase) and/or a slower transcellular diffusi on coefficient. They are therefore anticipated to be absorbed through the paracellular route, which is a consequence of diffusion and a conv ective volume flow through the water-filled intercellular space. Metho ds. Two approaches have been used to investigate the mechanisms underl ying the paracellular drug transport across the intestinal mucosa: (a) including water transport by exposing the apical side of the epitheli um with a hypotonic solution, and (b) stimulated paracellular transpor t by widening of tight junction and increased water absorption as a co nsequence of the sodium-coupled transport of nutrients. Results. Among the first studies that recognized this fluid flux dependent transmuco sal transport of drugs, was one published by Oschenfahrt & Winne in 19 73 and the one by Kitazawa et al. in 1975. During the last two decades the importance of this paracellular route for drug delivery have been explored in vitro and in situ. Conclusions. The limits concerning mol ecular weight, shape, ionization and the effect of physiological stimu lants, such as luminal concentrations of nutrients, osmolality and mot ility, are currently under investigation. However, recently published in vivo human data by ourselves and others indicate that the promising results obtained in vitro and in situ for various hydrophilic compoun ds might not be valid in quantitative aspects in humans, especially no t for drugs with a molecular weight over 200.