The Impact of Molecular Complexation on Intestinal Membrane Permeation.

Membrane Transport;Effect of Complexation on Permeability;Ion-pairing;Permeability Enhancement by Ion-pairing;Effect of Cyclodextrin on Permeability;Pharmacy and Pharmacology;Health Sciences;Pharmaceutical Sciences

Miller, Jonathan MarkWang, Henry Yee-Neen ;

University of Michigan

关键词: Membrane Transport;    Effect of Complexation on Permeability;    Ion-pairing;    Permeability Enhancement by Ion-pairing;    Effect of Cyclodextrin on Permeability;    Pharmacy and Pharmacology;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/63849/jonmille_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

This dissertation focuses on the impact of molecular complexation on intestinal membrane permeation. Two cases in which molecular complexation in solution affects intestinal membrane transport are considered: 1) enhancement of membrane transport of low-permeability drugs through ion-pairing with lipophilic counterions and 2) reduction of apparent permeability of low-solubility drugs as a consequence of complexation with cyclodextrins. Quasi-equilibrium mass-transport analyses were developed to describe: 1) the ion-pair mediated octanol-buffer partitioning and membrane permeation of the low-permeability drugs phenformin, GS 4109, and zanamivir-heptyl-ester and 2) the effect of cyclodextrins on the membrane transport of the low-solubility drug progesterone. The counterion 1-hydroxy-2-naphthoic acid (HNAP) enhanced the lipophilicity of the low-permeability drugs by up to 3.7 log units. As predicted from a quasi-equilibrium analysis of ion-pair mediated membrane transport, a log increase in permeability was observed per log increase in HNAP concentration in the parallel artificial membrane permeation (PAMPA) and Caco-2 monolayer assays. Only the rat jejunal permeability of zanamivir heptyl ester was enhanced by HNAP and this was explained by its stronger binding constant (388 M-1) as compared to the phenformin-HNAP and GS 4109-HNAP ion-pairs (3 M-1). Key attributes for successful ion-pair mediated membrane transport were proposed: 1) ion-pair log PAB value in the range of 2-5 to provide sufficient lipophilicity and 2) strong aqueous binding constant on the order of 100-1000 M-1 to prevent ion-pair dissociation during membrane permeation.The transport analysis quantitatively predicted the apparent permeability decrease of progesterone with increasing cyclodextrin concentration (Ccd) in the PAMPA, Caco-2 monolayer, and rat jejunal perfusion assays. The model considers the effect of Ccd on both the apparent membrane permeability (Pm) and aqueous boundary layer permeability (Paq). The model revealed that: 1) Paq increases with increasing Ccd, as the boundary layer thickness quickly decreases as the progesterone bound fraction increases and 2) Pm decreases with increasing Ccd, due to the decrease in progesterone free fraction.In summary, this work provides an increased understanding of the underlying mechanisms that govern the effects of molecular complexation on intestinal membrane transport, and enables the more efficient and intelligent use of molecular complexation strategies to facilitate oral absorption.