Computational oral absorption simulation for low-solubility compounds.

Bile micelles play an important role in oral absorption of low-solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH-solubility profile in bile micelles, the Henderson-Hasselbalch equation should be modified to take bile-micelle partition into account. For the dissolution rate, in the Nernst-Brunner equation, the effective diffusion coefficient in bile-micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8- to 18-fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral-absorption data of low-solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.