Recent Experimental Developments in Studying Passive Membrane Transport of Drug Molecules

Gh., Mohammad Sharifian

doi:10.1021/acs.molpharmaceut.1c00009

Cited by 29 publications

(29 citation statements)

References 314 publications

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“…Concentrations of drugs in each acceptor well were quantified either by highperformance liquid chromatography-ultraviolet (HPLC-UV) or high-performance liquid chromatography-mass spectrometry (HPLC-MS). The apparent permeability coefficient (P app ) was expressed using eq 1 derived from Fick's law 34 for steadystate conditions…”

Section: Methodsmentioning

confidence: 99%

“…Concentrations of drugs in each acceptor well were quantified either by high-performance liquid chromatography-ultraviolet (HPLC-UV) or high-performance liquid chromatography-mass spectrometry (HPLC-MS). The apparent permeability coefficient ( P app ) was expressed using eq derived from Fick’s law for steady-state conditions where d Q is the quantity of drug expressed as moles permeated into acceptor compartment at time t (18 000 s), C 0 is the initial concentration in the donor well, and A is the area of the well membrane (0.3 cm 2 ). P app was used as an average of all of the measures.…”

Section: Methodsmentioning

confidence: 99%

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Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies

et al. 2021

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Mucus represents a strong barrier to tackle for oral or pulmonary administered drugs, especially in mucus-related disorders. This study uses a pathological cystic fibrosis (CF) mucus model to investigate how mucus impacts the passive diffusion of 45 ad hoc commercial drugs selected to maximize physicochemical variability. An in vitro mucosal surface was recreated by coupling the mucus model to a 96-well permeable support precoated with structured layers of phospholipids (parallel artificial membrane permeability assay, PAMPA). Results show that the mucus model was not a mere physical barrier but it behaves like an interactive filter. In nearly one-half of the investigated compounds, the diffusion was reduced by mucus, while other drugs were not sensitive to the mucus barriers. We also found that permeability can be enhanced when drug–calcium salts are formed. This was confirmed with cystic fibrosis sputum as a rough ex vivo model of CF mucus. Since the drug discovery process is characterized by a high rate of failure, the mucus platform is expected to provide an efficient support to early reduce the number of poor-performing drug candidates.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies

et al. 2021

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“…A web server and database PerMM is dedicated to gathering experimental and computational data related to small molecule membrane partitioning and translocation [578]. For a recent review of the development of experimental methods used for studying passive diffusion through membranes, see reference [579]. Regarding the study of drug translocation through the lipid bilayer, the main limitation is the time scale that is possible to reach with MD simulations with all atom resolution; this typically is not sufficient to allow for the observation of the entire translocation process without some form of force bias.…”

Section: Translocation Through the Membranementioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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“…A microcavity-supported lipid bilayer may offer a useful, low-cost alternative for studying drug interactions with the membrane during the early stages of drug development . Previously, in vitro platforms were used to anticipate passive membrane permeability and membrane-associated toxicological problems isolated from the complexity of the living cell. , Biomembrane models, such as liposomes and supported lipid bilayers (SLB), have been successfully applied to interrogate the interaction of membrane lipids with small molecules. − They have provided much insight, but there is still room for improvement in the biomimicry of the in vivo membrane. In the case of liposomes, they are limited to interfacial studies in two dimensions, while interference from the interfacial support due to pinning on the fluidity and functionality of the bilayer and associated proteins limits SLB biomimicry. − Several modifications have been developed that may decouple the proximal leaflet from the substrate while retaining membrane component mobility.…”

Section: Introductionmentioning

confidence: 99%

Multimodal Investigation into the Interaction of Quinacrine with Microcavity-Supported Lipid Bilayers

2022

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Quinacrine is a versatile drug that is widely recognized for its antimalarial action through its inhibition of the phospholipase enzyme. It also has antianthelmintic and antiprotozoan activities and is a strong DNA binder that may be used to combat multidrug resistance in cancer. Despite extensive cell-based studies, a detailed understanding of quinacrine’s influence on the cell membrane, including permeability, binding, and rearrangement at the molecular level, is lacking. Herein, we apply microcavity-suspended lipid bilayers (MSLBs) as in vitro models of the cell membrane comprising DOPC, DOPC:Chol(3:1), and DOPC:SM:Chol(2:2:1) to investigate the influence of cholesterol and intrinsic phase heterogeneity induced by mixed-lipid composition on the membrane interactions of quinacrine. Using electrochemical impedance spectroscopy (EIS) and surface-enhanced Raman spectroscopy (SERS) as label-free surface-sensitive techniques, we have studied quinacrine interaction and permeability across the different MSLBs. Our EIS data reveal that the drug is permeable through ternary DOPC:SM:Chol and DOPC-only bilayer compositions. In contrast, the binary cholesterol/DOPC membrane arrested permeation, yet the drug binds or intercalates at this membrane as reflected by an increase in membrane impedance. SERS supported the EIS data, which was utilized to gain structural insights into the drug–membrane interaction. Our SERS data also provides a simple but powerful label-free assessment of drug permeation because a significant SERS enhancement of the drug’s Raman signature was observed only if the drug accessed the plasmonic interior of the pore cavity passing through the membrane. Fluorescent lifetime correlation spectroscopy (FLCS) provides further biophysical insight, revealing that quinacrine binding increases the lipid diffusivity of DOPC and the ternary membrane while remarkably decreasing the lipid diffusivity of the DOPC:Chol membrane. Overall, because of its adaptability to multimodal approaches, the MSLB platform provides rich and detailed insights into drug–membrane interactions, making it a powerful tool for in vitro drug screening.

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Recent Experimental Developments in Studying Passive Membrane Transport of Drug Molecules

Cited by 29 publications

References 314 publications

Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies

Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Multimodal Investigation into the Interaction of Quinacrine with Microcavity-Supported Lipid Bilayers

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