Profiling and Trend Analysis of Food Effects on Oral Drug Absorption Considering Micelle Interaction and Solubilization by Bile Micelles

Abstract

Correlation analysis between food effects on oral drug absorption (food effect) and physicochemical properties is important for efficient drug discovery and contributes to drug design. This study focused on micelle binding and solubilization considering bile micelles in the intestinal fluid. Profiling using about 40 launched drugs demonstrated that those in a high solubilization area (area 1) tended to have a positive food effect, and that drugs exhibiting negative/no food effect tended to coexist in a no/low solubilization area (area 2). In area 1, the solubilization effect by bile micelles was demonstrated quantitatively as an important factor that indicates a positive food effect. In area 2, the relative and quantitative relationships among the membrane permeation rate, dissolution rate, micelle binding and food effect could be clarified by simulation. The improvement of membrane permeability and the suppression of micelle binding are considered to be required to avoid a negative food effect. In conclusion, important factors contributing to the food effect were clarified relatively and quantitatively. Data generated from this profiling may be beneficial to find a solution for negative food effects. Furthermore, this risk assessment of food effects is considered to be a useful tool in rational drug design for drug discovery.

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

“…In the epithelial membrane permeability limited (PL‐E) cases, a negative food effect can be observed. Bile micelle binding reduces the unbound drug concentration at the epithelial surface and reduces the effective permeability of a drug . In the solubility–epithelial membrane permeability limited (SL‐E) cases, Fa would not be increased by bile micelles.…”

“…Bile micelle binding reduces the unbound drug concentration at the epithelial surface and reduces the effective permeability of a drug. [42][43][44] In the solubility-epithelial membrane permeability limited (SL-E) cases, Fa would not be increased by bile micelles. The drug molecules bound to bile micelles cannot permeate across the epithelial cell membranes.…”

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

“…BMS-F and BMS-H are examples of such compounds where it is generally thought that the physical entrapment of the drug in the viscous, post-prandial GI fluid milieu leads to unavailability of free drug for absorption through the paracellular junctions (29). Kawai et al (37) reported that hydrophilic drugs that dissolve rapidly are more likely to be limited by their permeation rates due to physical interaction with food components in the fed state. In this study, both BMS-F and BMS-H show rapid dissolution, although, the reason for reduced dissolution in FeSSIF was not investigated further.…”

“…The former can be diagnosed by analytical techniques such as contact angle measurement for drug wettability. The latter can be tested for sequestration in bile, a situation for high log P drugs that show good bile micelle solubilization, but poor absorption at the epithelial surface due to unavailability of free drug (6,37).…”

The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers

“…The extent of absorption of orally administered drugs with or without food appears to be determined by the drug's solubility and membrane permeability, among other parameters [1]. Administration of certain drugs with food has the potential to dramatically alter drug absorption, especially after meals with a high fat content [2].…”