Clinical Utility of Free Drug Monitoring

Musteata, Florin Marcel

doi:10.1016/b978-0-12-385467-4.00004-x

Cited by 7 publications

(6 citation statements)

References 61 publications

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“…From K bind values it was determined a PPB of 94.76% (Equation 8) meaning that a major part of AntiOxCIN 3 in solution is bound to HSA leaving only 5.24% of the free AntiOxCIN 3 available to be distributed to the tissues. 46 The magnitude of these values is indicative of a strong interaction between AntiOxCIN 3 and HSA. 45 Additionally, from the application of a linear fit of data according to van't Hoff equation (Figure S2B), the thermodynamic parameters of the interaction were determined (Equations 9 and 10).…”

Section: Results and Discussion Interaction Studies With Micelles Modmentioning

confidence: 99%

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Lipid Nanosystems and Serum Protein as Biomimetic Interfaces: Predicting the Biodistribution of a Caffeic Acid-Based Antioxidant

Fernandes

Benfeito

Cagide

et al. 2021

NSA

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AntiOxCIN 3 is a novel mitochondriotropic antioxidant developed to minimize the effects of oxidative stress on neurodegenerative diseases. Prior to an investment in preclinical in vivo studies, it is important to apply in silico and biophysical cell-free in vitro studies to predict AntiOxCIN 3 biodistribution profile, respecting the need to preserve animal health in accordance with the EU principles (Directive 2010/63/EU). Accordingly, we propose an innovative toolbox of biophysical studies and mimetic models of biological interfaces, such as nanosystems with different compositions mimicking distinct membrane barriers and human serum albumin (HSA). Methods: Intestinal and cell membrane permeation of AntiOxCIN 3 was predicted using derivative spectrophotometry. AntiOxCIN 3-HSA binding was evaluated by intrinsic fluorescence quenching, synchronous fluorescence, and dynamic/electrophoretic light scattering. Steady-state and time-resolved fluorescence quenching was used to predict AntiOxCIN 3membrane orientation. Fluorescence anisotropy, synchrotron small-and wide-angle X-ray scattering were used to predict lipid membrane biophysical impairment caused by AntiOxCIN 3 distribution. Results and Discussion: We found that AntiOxCIN 3 has the potential to permeate the gastrointestinal tract. However, its biodistribution and elimination from the body might be affected by its affinity to HSA (>90%) and by its steady-state volume of distribution (VD SS =1.89 ± 0.48 L•Kg −1). AntiOxCIN 3 is expected to locate parallel to the membrane phospholipids, causing a bilayer stiffness effect. AntiOxCIN 3 is also predicted to permeate through blood-brain barrier and reach its therapeutic target-the brain. Conclusion: Drug interactions with biological interfaces may be evaluated using membrane model systems and serum proteins. This knowledge is important for the characterization of drug partitioning, positioning and orientation of drugs in membranes, their effect on membrane biophysical properties and the study of serum protein binding. The analysis of these interactions makes it possible to collect valuable knowledge on the transport, distribution, accumulation and, eventually, therapeutic impact of drugs which may aid the drug development process.

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Section: Results and Discussion Interaction Studies With Micelles Modmentioning

confidence: 99%

“…where C P is the physiological plasma protein concentration (750 μM). 46 Furthermore, the next equation describes the relation between K bind value and the Gibbs free energy (ΔG) of the binding complex by:…”

mentioning

confidence: 99%

Lipid Nanosystems and Serum Protein as Biomimetic Interfaces: Predicting the Biodistribution of a Caffeic Acid-Based Antioxidant

Fernandes

Benfeito

Cagide

et al. 2021

NSA

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“…where PPB can be obtained from the in vitro values of K bind [33]: (14) where C P is the physiological plasma protein concentration (750 µM) [33].…”

Section: Modelling Biodistribution Using In Vitro Parametersmentioning

confidence: 99%

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

et al. 2021

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Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 ± 0.932 L·Kg−1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

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“…where CP is the physiological plasma protein concentration (750 µM) [35]. Lastly, fut can be obtained by the following equation [34]:…”

Section: Modelling Biodistribution Using In Vitro Parametersmentioning

confidence: 99%

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

Almeida¹,

Fernandes²,

Sarmento³

et al. 2021

Preprint

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Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood-brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS=5.75 ± 0.932 L·Kg-1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

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Clinical Utility of Free Drug Monitoring

Cited by 7 publications

References 61 publications

Lipid Nanosystems and Serum Protein as Biomimetic Interfaces: Predicting the Biodistribution of a Caffeic Acid-Based Antioxidant

Lipid Nanosystems and Serum Protein as Biomimetic Interfaces: Predicting the Biodistribution of a Caffeic Acid-Based Antioxidant

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

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