Computational Oral Absorption Simulation for Low‐Solubility Compounds

Abstract

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.

Differences in Food Effects for 2 Weak Bases With Similar BCS Drug-Related Properties: What Is Happening in the Intestinal Lumen?

“…Briefly, using a built-in quantitative structureeactivity relationship model based on Glomme et al to calculate the bile micelle:water partition coefficient of the drug (K m:w ) from LogP, the software applies bile micelleemediated solubilization enhancement to calculate in vivo drug solubility throughout the GIT from an experimental or predicted drug pH solubility profile. 37,38 The predictions from the QSAR model using drug pKa and intrinsic solubility (S 0 ) can be compared to experimental biorelevant solubilities and the predicted K m:w can be manually adjusted, if required, to match the observed values. Because ketoconazole was used to train the model 37 and given that posaconazole is a structurally related compound, no further adjustments were made for either of these drugs and the estimated log K m:w values are reported in Table 1.…”

Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory and Applications

“…The Fa equation and FaCS have been applied to elucidate the food effect by bile micelles . In the DRL cases, the solubilization of a drug by bile micelles would increase the dissolution rate, leading to a positive food effect.…”

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

“…In order to predict oral PK, a mechanistic absorption model is required (54)(55)(56). These models rely on a variety of in vitro and/or in silico input data such as solubility, permeability, particle size, lipophilicity, pKa and dose, together with a series of differential equations to model the kinetics associated with dissolution, precipitation, uptake and absorption of a compound as it transits through the different (57)(58)(59).…”