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Diffusion equation for the longitudinal spectral diffusion: the case of the RIDME experiment.

ABSTRACT: Relaxation-induced dipolar modulation enhancement (RIDME) time trace shapes reveal linear scaling with the proton concentration in homogeneous glassy samples. We describe here an approximate diffusion equation-based analysis of such data, which uses only two fit parameters and allows for global data fitting with good accuracy. By construction, the approach should be transferable to other pulse EPR experiments with longitudinal mixing block(s) present. The two fit parameters appear to be sensitive to the type of the glassy matrix and can be thus used for sample characterisation. The estimates suggest that the presented technique should be sensitive to protons at distances up to 3 nm from the electron spin at a 90% matrix deuteration level. We propose that a structural method might be developed based on such an intermolecular hyperfine (ih-)RIDME technique, which would be useful, for instance, in structural biology or dynamic nuclear polarisation experiments.

SUBMITTER: Kuzin S

PROVIDER: S-EPMC9533373 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Diffusion equation for the longitudinal spectral diffusion: the case of the RIDME experiment.

Kuzin Sergei S Jeschke Gunnar G Yulikov Maxim M

Physical chemistry chemical physics : PCCP 20221005 38

Relaxation-induced dipolar modulation enhancement (RIDME) time trace shapes reveal linear scaling with the proton concentration in homogeneous glassy samples. We describe here an approximate diffusion equation-based analysis of such data, which uses only two fit parameters and allows for global data fitting with good accuracy. By construction, the approach should be transferable to other pulse EPR experiments with longitudinal mixing block(s) present. The two fit parameters appear to be sensitiv ...[more]

PMID: 36129124

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Project description:Prediction of the rate and extent of drug absorption upon oral dosing needs models that capture the complexities of both the drug molecule and intestinal physiology. We report here the development of a continuous intestinal absorption model based on the convection-diffusion equation. The model includes explicit enterocyte apical membrane and intracellular lipid radial compartments along the length of the intestine. Physiologic functions along length x are built into the model and include velocity, diffusion, surface areas, and pH of the intestine. Also included are expression levels of the intestinal active uptake transporter OATP2B1 and efflux transporter P-gp. Oral dosing of solution as well as solid (with a dissolution function) was modeled for several drugs. The fraction absorbed (FA) and concentration-time (C-t) profiles were predicted and compared with clinical data. Overall, FA was well predicted upon oral (n = 21) or colonic dosing (n = 11), with four outliers. The overall accuracy (prediction of the correct bin) was 81% with outliers and 90% without outliers. Of the nine solution dosing data sets, six drugs were very well predicted with an exposure overlap coefficient (EOC) > 0.9 and predicted Cmax and Tmax values similar to those observed. Of the six solid dose formulations evaluated, the EOC values were > 0.9 for all drugs except budesonide. The observed precipitation of nifedipine at high doses was predicted by the model. Most of the poor predictions were for drugs that are known to be transporter substrates. As proof of concept, incorporating OATP2B1 and P-gp markedly improved the EOC and predicted Cmax and Tmax for fexofenadine. Finally, the continuous intestinal model accurately recapitulated the known relationships between drug absorption and permeability, solubility, and particle size. Together, these results indicate that this preliminary intestinal absorption model offers a simple and straightforward framework to build in complexities such as drug permeability, lipid partitioning, solubility, metabolism, and transport for improved prediction of the rate and extent of drug absorption.

Dataset Information

Diffusion equation for the longitudinal spectral diffusion: the case of the RIDME experiment.

Publications

Diffusion equation for the longitudinal spectral diffusion: the case of the RIDME experiment.

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