How relevant are assembled equilibrium samples in understanding structure formation during lipid digestion?

Phan, Stephanie; Salentinig, Stefan; Hawley, Adrian; Boyd, Ben J.

doi:10.1016/j.ejpb.2015.07.015

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…Many of these studies have looked at changes in micelle structure as well as formation of crystalline phases at the oil emulsion interface, some of them using synchrotron SAXS to allow detection of structures throughout lipolysis [21–26]. Such studies have been informative in developing a physical conceptual model of the dynamic intestinal milieu.…”

Section: Introductionmentioning

confidence: 99%

Characterization of colloidal structures during intestinal lipolysis using small-angle neutron scattering

Rezhdo

Maio

et al. 2017

Journal of Colloid and Interface Science

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Hypothesis Bile micelles are thought to mediate intestinal absorption, in part by providing a phase into which compounds can partition. Solubilizing capacity of bile micelles is enhanced during the digestion of fat rich food. We hypothesized that the intestinal digestion of triglycerides causes an increase in volume of micelles that can be quantitatively monitored over the course of digestion using small-angle neutron scattering (SANS), and that SANS can enable evaluation of the contribution of each of the components present during digestion to the size of micelles. Experiments SANS was used to characterize the size and shape of micelles present prior to and during the in vitro simulated intestinal digestion of a model food-associated lipid, triolein. Findings Pre-lipolysis mixtures of a bile salt and phospholipid simulating bile concentrations in fed conditions were organized in micelles with an average volume of 40 nm3. During lipolysis, the micelle volume increased 2.5-fold over a 2-hour digestion period due to growth in one direction as a result of insertion of monoglycerides and fatty acids. These efforts represent a basis for quantitative mechanistic understanding of changes in solubilizing capacity of the intestinal milieu upon ingestion of a fat-rich meal.

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Section: Introductionmentioning

confidence: 99%

Characterization of colloidal structures during intestinal lipolysis using small-angle neutron scattering

Rezhdo

Maio

et al. 2017

Journal of Colloid and Interface Science

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“…179 angle X-ray scattering, coherent anti-Stokes Raman spectroscopy, and surface plasmon resonance would promote understanding of membrane transport, drug-colloidal structures interactions, lipid imaging at the molecular level, drug or excipient release, disposition, and intracellular concentrations. 83,84,186,187 Thus, a plethora of opportunities not only for GI imaging but also for the development of data analysis and in silico tools, which will be interacting or even be integrated into PBPK models, is foreseen. Supporting these efforts, further integration of PBPK with pharmacometrics is more than essential.…”

Section: ■ Opportunities and Future Actionsmentioning

confidence: 99%

“…Additionally, there are several, yet to be answered, questions associated with micelle-mediated solubilization and in vivo precipitation. Understanding of the relative contribution of bile and/or food components on the solubilization of drug substances, the partitioning between the micellar and aqueous phase and the biophysical interactions of drug molecules with the micellar structures is perceived as a promising area of research. − At the same time, the mechanisms of in vivo supersaturation, precipitation, and redissolution and their interplay with drug permeation and transport deserve further investigation. ,− Several bioenabling formulations have been developed to enhance oral bioavailability such as nanoparticles, self-emulsifying drug delivery systems, cyclodextrin complexes, solid dispersions, and lipid-based formulations . For instance, the effects of lipolysis on drug release from lipid-based formulations in vivo are unknown, , while the penetration of the intestinal mucosa by nanoparticles, , as well as the uptake of dendrimer-drug conjugates and their transepithelial transport, are still an area of speculation …”

Section: Knowledge Gaps Challenges and Limitationsmentioning

confidence: 99%

“…Several advanced, preferably noninvasive and real-time, imaging technologies have been adopted to overcome this hurdle, but further progress is still required. Magnetic resonance (MR), contrast-enhanced MR, computed tomography (CT) and nuclear imaging, capsule endoscopy, 3D endoscope imaging, high-resolution electrical mapping, and electrogastrogram have been used to visualize the gut lumen (patho)-physiology and gain insight into the in vivo behavior of drug/formulation in preclinical species, healthy humans, and patients. − Furthermore, systematic exploration of the capabilities of molecular dynamics (MD) simulations, synchrotron small-angle X-ray scattering, coherent anti-Stokes Raman spectroscopy, and surface plasmon resonance would promote understanding of membrane transport, drug-colloidal structures interactions, lipid imaging at the molecular level, drug or excipient release, disposition, and intracellular concentrations. ,,, Thus, a plethora of opportunities not only for GI imaging but also for the development of data analysis and in silico tools, which will be interacting or even be integrated into PBPK models, is foreseen.…”

Section: Opportunities and Future Actionsmentioning

confidence: 99%

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Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

Loisios-Konstantinidis

Dressman

2020

Mol. Pharmaceutics

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Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been extensively applied to quantitatively translate in vitro data, predict the in vivo performance, and ultimately support waivers of in vivo clinical studies. In the area of biopharmaceutics and within the context of model-informed drug discovery and development (MID3), there is a rapidly growing interest in applying verified and validated mechanistic PBPK models to waive in vivo clinical studies. However, the regulatory acceptance of PBPK analyses for biopharmaceutics and oral drug absorption applications, which is also referred to variously as “PBPK absorption modeling” [CPT: Pharmacometrics Syst. Pharmacol.20176492], “physiologically based absorption modeling”, or “physiologically based biopharmaceutics modeling” (PBBM), remains rather low [J. Pharm. Sci.20161052723] [AAPS J.20192129]. Despite considerable progress in the understanding of gastrointestinal (GI) physiology, in vitro biopharmaceutic and in silico tools, PBPK models for oral absorption often suffer from an incomplete understanding of the physiology, overparameterization, and insufficient model validation and/or platform verification, all of which can represent limitations to their translatability and predictive performance. The complex interactions of drug substances and (bioenabling) formulations with the highly dynamic and heterogeneous environment of the GI tract in different age, ethnic, and genetic groups as well as disease states have not been yet fully elucidated, and they deserve further research. Along with advancements in the understanding of GI physiology and refinement of current or development of fully mechanistic in silico tools, we strongly believe that harmonization, interdisciplinary interaction, and enhancement of the translational link between in vitro, in silico, and in vivo will determine the future of PBBM. This Perspective provides an overview of the current status of PBBM, reflects on challenges and knowledge gaps, and discusses future opportunities around PBPK/PD models for oral absorption of small and large molecules to waive in vivo clinical studies

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“…8 For instance, emulsions formed by medium chain triglycerides transition to vesicles upon digestion; 9 monoolein based cubosomes transition from inverse cubic through a variety of inverse nanostructures to dispersed oil droplets upon hydrolysis; 10 milk emulsions (triglycerides) transition to a variety of differently ordered nanostructures. 8,11 The selective lipolysis of lipids from the interface of lipidic particles can also direct the phase transitions, [12][13] where the products of hydrolysis align themselves within the lipid bilayer according to their physicochemical properties. 14 Towards the development of enzyme-responsive lipid-based nanomaterials as drug delivery systems, this study seeks to understand the changes in nanostructure of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) based particles under the action of phospholipase C (PLC); an interfacially active enzyme that was until recently viewed only as an instrument of lipidic degradation.…”

Section: Introductionmentioning

confidence: 99%

Structural Transformation in Vesicles upon Hydrolysis of Phosphatidylethanolamine and Phosphatidylcholine with Phospholipase C

et al. 2019

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This study provides insight into dynamic nanostructural changes in phospholipid systems during hydrolysis with phospholipase C, the fate of the hydrolysis products and the kinetics of lipolysis. The effect of lipid restructuring of the vesicle was investigated using small-angle X-ray scattering and cryogenic scanning electron microscopy. The rate and extent of phospholipid hydrolysis was quantified using NMR. Hydrolysis of two phospholipids, phosphatidylethanolamine and phosphatidylcholine, results in the cleavage of the molecular headgroup, causing two strikingly different changes in lipid self-assembly. The diacylglycerol product of phosphatidylcholine escapes the lipid bilayer, whereas the diacylglycerol product adopts a different configuration within the lipid bilayer of the phosphatidylethanolamine vesicles. These results are then discussed concerning the change of lipid configuration upon the lipid membrane and its potential implications in vivo, which is of significant importance for the detailed understanding of the fate of lipidic particles and the rational design of enzyme-responsive lipid-based drug delivery systems.

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How relevant are assembled equilibrium samples in understanding structure formation during lipid digestion?

Cited by 10 publications

References 46 publications

Characterization of colloidal structures during intestinal lipolysis using small-angle neutron scattering

Characterization of colloidal structures during intestinal lipolysis using small-angle neutron scattering

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

Structural Transformation in Vesicles upon Hydrolysis of Phosphatidylethanolamine and Phosphatidylcholine with Phospholipase C

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