Drug D i s t r i b u t i o n. Pa r t 1. M o d e l s t o P r e d i c t Membrane Partitioning

作者：Nagar Swati; Korzekwa Ken^*

来源：Pharmaceutical Research, 2017, 34(3): 535-543.

DOI：10.1007/s11095-016-2085-z

• drug distribution
• microsomal partitioning
• molecular modeling

Purpose Tissue partitioning is an important component of drug distribution and half-life. Protein binding and lipid partitioning together determine drug distribution.
Methods Two structure-based models to predict partitioning into microsomal membranes are presented. An orientation-based model was developed using a membrane template and atom-based relative free energy functions to select drug conformations and orientations for neutral and basic drugs.
Results The resulting model predicts the correct membrane positions for nine compounds tested, and predicts the membrane partitioning for n = 67 drugs with an average fold-error of 2.4. Next, a more facile descriptor-based model was developed for acids, neutrals and bases. This model considers the partitioning of neutral and ionized species at equilibrium, and can predict membrane partitioning with an average fold-error of 2.0 (n = 92 drugs).
Conclusions Together these models suggest that drug orientation is important for membrane partitioning and that membrane partitioning can be well predicted from physicochemical properties.

• 出版日期2017-3