Novel In-Vitro Approaches to Investigate Membrane Partitioning and pH-Dependent Passive Permeation of Small Molecule Drugs
type: CreativeWork
description: Passive permeability of drug molecules through biological membranes is a fundamentally important process that involves the partitioning of molecules into the lipid bilayer membrane and passive permeation across the membrane. The majority of the drug molecules are either weak bases or acids. For these drugs, along with lipophilicity and other physicochemical properties, the acid/base nature and ionization constant (pKa) are very important for predicting their passive permeation across biological barriers. Depending on the pKa of ionizable groups, drug molecules may coexist in various biological fluids both their charged and uncharged forms to varying extents. According to the widely known pH-partition hypothesis, only the uncharged form of ionizable molecules contributes to the passive permeability. Therefore, permeability and absorption rate should be proportional to the molar fraction of the uncharged form in the bulk medium. However, there is ample evidence of deviations from this linear relationship manifesting in nonlinear passive permeability vs fraction unionized plots. It is possible that the assumption of a constant pKa for ionizable drugs contributes to many of these cases of apparent deviations which cannot be explained by other factors such as paracellular or active transport. Studies have provided evidence for pKa shifts of ionizable drugs when partitioned into different bilayer lipid membrane systems.It is thought that electrostatic interaction between the membrane partitioned charged solutes and phospholipid charged headgroups contributes to the pKa shift (apparent pKa) which can change the uncharged fraction in the membrane interface causing a proportional change in the passive permeation rate from the expected rate predicted with an aqueous pKa. This would appear as a violation of the pH-partition hypothesis when other contributing factors can be ruled out. Therefore, a surrogate membrane phospholipid system (DAPC/n-hexane) was employed to investigat…
abstract: Passive permeability of drug molecules through biological membranes is a fundamentally important process that involves the partitioning of molecules into the lipid bilayer membrane and passive permeation across the membrane. The majority of the drug molecules are either weak bases or acids. For these drugs, along with lipophilicity and other physicochemical properties, the acid/base nature and ionization constant (pKa) are very important for predicting their passive permeation across biological barriers. Depending on the pKa of ionizable groups, drug molecules may coexist in various biological fluids both their charged and uncharged forms to varying extents. According to the widely known pH-partition hypothesis, only the uncharged form of ionizable molecules contributes to the passive permeability. Therefore, permeability and absorption rate should be proportional to the molar fraction of the uncharged form in the bulk medium. However, there is ample evidence of deviations from this linear relationship manifesting in nonlinear passive permeability vs fraction unionized plots. It is possible that the assumption of a constant pKa for ionizable drugs contributes to many of these cases of apparent deviations which cannot be explained by other factors such as paracellular or active transport. Studies have provided evidence for pKa shifts of ionizable drugs when partitioned into different bilayer lipid membrane systems.It is thought that electrostatic interaction between the membrane partitioned charged solutes and phospholipid charged headgroups contributes to the pKa shift (apparent pKa) which can change the uncharged fraction in the membrane interface causing a proportional change in the passive permeation rate from the expected rate predicted with an aqueous pKa. This would appear as a violation of the pH-partition hypothesis when other contributing factors can be ruled out. Therefore, a surrogate membrane phospholipid system (DAPC/n-hexane) was employed to investigat…
author: Hridoy, Md
language: eng
keywords: Pharmaceutical sciences, Cellular drug distribution, In vitro microdialysis, Membrane partitioning, Membrane pKa shift, Passive permeability, pH-partition hypothesis
license: http://rightsstatements.org/vocab/InC/1.0/
date published: 2023-12
date modified: 2026-07-27T21:22:14Z
provider: Temple University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Temple University. Libraries

PropertyValue
property ID: Handle
value: http://hdl.handle.net/20.500.12613/10351