FCCC LOGO Faculty Publications
Nagar S , Korzekwa K
Drug Distribution. Part 1. Models to Predict Membrane Partitioning
Pharm Res. 2017 Mar;34(3) :535-543
PMID: 27981450    PMCID: PMC5588161   
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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.
1573-904x Nagar, Swati Korzekwa, Ken ORCID: http://orcid.org/0000-0002-7119-9200 R01 GM104178/GM/NIGMS NIH HHS/United States R01 GM114369/GM/NIGMS NIH HHS/United States Journal Article United States Pharm Res. 2017 Mar;34(3):535-543. doi: 10.1007/s11095-016-2085-z. Epub 2016 Dec 15.