Drug Partitioning and Solvation Environments in Lipid Bilayers

partitioning;QSAR;lipid bilayer;liposome

Carrozzino, Jennifer Marie ; Edmond F. Bowden, Committee Member,Morteza G. Khaledi, Committee Chair,Charles B. Boss, Committee Member,Daniel L. Feldheim, Committee Member,Carrozzino, Jennifer Marie ; Edmond F. Bowden ; Committee Member ; Morteza G. Khaledi ; Committee Chair ; Charles B. Boss ; Committee Member ; Daniel L. Feldheim ; Committee Member

University:North Carolina State University

关键词: partitioning;    QSAR;    lipid bilayer;    liposome;   

Others  :  https://repository.lib.ncsu.edu/bitstream/handle/1840.16/4850/etd.pdf?sequence=1&isAllowed=y

美国|英语

来源: null

【 摘 要 】

The main goal of this research project was to investigate various factors influencing solute partitioning and solvation in lipid bilayer membranes using liposomes as biomembrane models and applying a combination of spectroscopic and capillary electrophoresis techniques.The first area of investigation involved using a series of polarity sensitive solvatochromic indicators to probe the dipolarity of various phospholipid and synthetic surfactant vesicles. A homologous series of probes of varying hydrophobicity allowed a systematic probing of the dipolarity in the interfacial region of the vesicles and resulted in very specific polarity information for various regions or microenvironments depending on the probes positions. This dipolarity was examined in terms of vesicle size and composition, in addition to indicator partitioning behavior.To develop Liposome Electrokinetic Chromatography (LEKC) as a method for rapidly determining liposome - water distribution coefficients, the effects of various parameters on the retention of basic drugs in liposomes were examined. This included characterizing the electrostatics of interactions between charged drugs and charged lipid membranes by examining the effect of membrane and buffer compositions. Additionally, LEKC was used to determine the effect of pH on the partitioning of basic drugs into liposomes composed of lipids which mimic the composition of natural cell membranes. Drug partitioning as a function of pH is examined in detail in terms of the fractions of charged and neutral drug forms in the aqueous and lipid phases. An increase in pH results in a smaller degree of ionization of the basic drugs and consequently leads to a lower degree of interaction with the negatively charged membranes.Finally, LEKC retention was used in QSAR studies for the evaluation of membrane permeability and intestinal absorption. LEKC retention factor data was correlated with human oral absorption in comparison with other methods such as octanol - water partitioning, total number of hydrogen bonding groups, and polar surface area. LEKC retention data was also related to Caco-2, MDCK, and human jejunal permeability in comparison with the standard model, octanol - water partitioning.