Molecular dynamics simulations reveal membrane interactions for poorly water-soluble drugs : impact of bile solubilization and drug aggregation
| Autor: | Aleksei Kabedev, Shakhawath Hossain, Madlen Hubert, Per Larsson, Christel A. S. Bergström |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Absorption (pharmacology)
Chemistry Pharmaceutical Drug-membrane interactions Pharmaceutical Science Micelle-membrane interaction 02 engineering and technology Molecular Dynamics Simulation Molecular dynamics 030226 pharmacology & pharmacy Micelle Amorphous aggregates 03 medical and health sciences Colloid Pharmaceutical Sciences 0302 clinical medicine Adsorption Monolayer Bile Lipid bilayer Micelles Intestinal fluid Chemistry Water 021001 nanoscience & nanotechnology Farmaceutiska vetenskaper Membrane Solubility Biophysics 0210 nano-technology |
| Popis: | Molecular transport mechanisms of poorly soluble hydrophobic drug compounds to lipid membranes were investigated using molecular dynamics (MD) simulations. The model compound danazol was used to investigate the mechanism(s) by which bile micelles delivered it to the membrane. The interactions between lipid membrane and pure drug aggregates-in the form of amorphous aggregates and nanocrystals-were also studied. Our simulations indicate that bile micelles formed in the intestinal fluid may facilitate danazol incorporation into cellular membranes through two different mechanisms. The micelle may be acting as: i) a shuttle that presents the danazol directly to the membrane or ii) an elevator that moves the solubilized danazol with it as the colloidal structure itself becomes incorporated and solubilized within the membrane. The elevator hypothesis was supported by complementary lipid monolayer adsorption experiments. In these experiments, colloidal structures formed with simulated intestinal fluid were observed to rapidly incorporate into the monolayer. Simulations of membrane interaction with drug aggregates showed that both the amorphous aggregates and crystalline nanostructures incorporated into the membrane. However, the amorphous aggregates solubilized more quickly than the nanocrystals into the membrane, thereby improving the danazol absorption. |
| Databáze: | OpenAIRE |
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