Understanding of Relationship between Phospholipid Membrane Permeability and Self-Diffusion Coefficients of Some Drugs and Biologically Active Compounds in Model Solvents

Blokhina, Svetlana V.; Volkova, Тatyana V.; Golubev, Vasiliy A.; Perlovich, German L.

doi:10.1021/acs.molpharmaceut.7b00401

Cited by 16 publications

(6 citation statements)

References 39 publications

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“…However, for the experimental conditions employed in this work, the standard diffusion equation resulted adequate (fitting error below 1%). Moreover, the experimental data results are quite comparable with the available literature data (refs − , linear fitting R 2 of 0.8). Due to the limited data available in the literature, it is difficult to clearly state if our method is more accurate than others.…”

Section: Resultssupporting

confidence: 87%

Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements

et al. 2018

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The diffusion coefficient (also known as diffusivity) of an active pharmaceutical ingredient (API) is a fundamental physicochemical parameter that affects passive diffusion through biological barriers and, as a consequence, bioavailability and biodistribution. However, this parameter is often neglected, and it is quite difficult to find diffusion coefficients of small molecules of pharmaceutical relevance in the literature. The available methods to measure diffusion coefficients of drugs all suffer from limitations that range from poor sensitivity to high selectivity of the measurements or the need for dedicated instrumentation. In this work, a simple but reliable method based on time-resolved concentration measurements by UV-visible spectroscopy in an unstirred aqueous environment was developed. This method is based on spectroscopic measurement of the variation of the local concentration of a substance during spontaneous migration of molecules, followed by standard mathematical treatment of the data in order to solve Fick's law of diffusion. This method is extremely sensitive and results in highly reproducible data. The technique was also employed to verify the influence of the environmental characteristics (i.e., ionic strength and presence of complexing agents) on the diffusivity. The method can be employed in any research laboratory equipped with a standard UV-visible spectrophotometer and could become a useful and straightforward tool in order to characterize diffusion coefficients in physiological conditions and help to better understand the drug permeability process.

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Section: Resultssupporting

confidence: 87%

Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements

et al. 2018

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“…The solubility–diffusion theory previously used in our studies [ 14 , 16 ] was applied to calculate the permeability coefficient by Equations (13)–(15), taking into account the heterogeneous structure of the lipophilic membrane. To this end, the permeability of the lipid and aqueous layers of the membrane was simulated using the diffusion coefficients of the compounds in 1-octanol and water, respectively, as well as the distribution coefficient in the 1-octanol/buffer pH 7.4 system.…”

Section: Resultsmentioning

confidence: 99%

“…Taking into account the numerous attempts to predict permeability reported in the literature [ 10 , 11 , 12 ] and our own experience [ 9 , 13 , 14 , 15 ], in the present study, we aimed to find a correlation between the permeability of a number of new fluconazole antifungal derivatives ( Figure 1 ), measured using the lipophilic PermeaPad barrier and several physicochemical properties and descriptors. In addition, we derived a reliable correlation equation for permeability prediction in the framework of the solubility–diffusion theory using the calculated diffusion coefficients in water and 1-octanol and the distribution coefficient in the 1-octanol/buffer pH 7.4 system determined experimentally in the literature [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling

Volkova

Perlovich

2023

Molecules

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Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier—a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility–diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.

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“…The calculated MSDs for Favipiravir and water are presented in Figure 5. The resulting self-diffusivities for Favipiravir and water are The calculated self-diffusion of Favipiravir in water has been presented in Table 4 together with the measured values of the self-diffusion of several representative pharmaceutical compounds in water, using several experimental techniques, which have already been presented in the literature 9,[43][44][45][46] . Taking into account that in general reported self-diffusion values may depend on the experimental technique and the force fields employed in simulation studies, the main purpose of this comparison is to demonstrate that the diffusion of Favipiravir in water is in a similar range with the diffusion of common painkillers and anti-inflammatory drugs (e.g.…”

Section: Resultsmentioning

confidence: 99%

Hydration Structure and Dynamics of the Favipiravir Antiviral Drug: A Molecular Modelling Approach

Skarmoutsos

Maurin

Guàrdia

et al. 2020

Bulletin of the Chemical Society of Japan

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The hydration structure of the Favipiravir antiviral drug, at infinite dilution in water, was investigated by employing a systematic molecular modelling approach. An effective interaction potential model was employed for Favipiravir, using the intramolecular geometry and charge distribution from quantum chemical calculations performed in the present treatment and adopting well-established Lennard-Jones parameters from the literature. The hydration structure and related dynamics were further investigated by means of classical molecular dynamics simulations. These calculations have revealed the existence of different types of hydrogen bonds between Favipiravir and the surrounding water molecules, with continuous lifetimes in the sub picosecond range and intermittent lifetimes in the range of 0.8-5.4 ps. The self-diffusion coefficient of Favipiravir of 9 2 1 0.58 10 m s − − ⋅ ⋅at 298.15 K was found to be three times lower than the value obtained for water in solution, while comparable to the to the values measured for other common painkillers and antiinflammatory drugs (e.g. paracetamol, aspirin, ketoprofen), antibiotics (e.g. tetracycline, trimethoprim, Penicillin G) and corticosteroids for asthma treatment (beclomethasone, prednisone).It was also revealed that the rotational motions of Favipiravir are more retarded in comparison with water and this is reflected on the calculated reorientational correlation times of specific intramolecular vectors. The results obtained in the present study could be useful in pharmaceutical applications, such as pharmacokinetics and computer-aided docking studies to evaluate the efficiency of this particular antiviral drug.

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Understanding of Relationship between Phospholipid Membrane Permeability and Self-Diffusion Coefficients of Some Drugs and Biologically Active Compounds in Model Solvents

Cited by 16 publications

References 39 publications

Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements

Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements

Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling

Hydration Structure and Dynamics of the Favipiravir Antiviral Drug: A Molecular Modelling Approach

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