scholarly journals Cross-Species Differential Plasma Protein Binding of MBX-102/JNJ39659100: A Novel PPAR- Agonist

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Holly J. Clarke ◽  
Francine Gregoire ◽  
Fang Ma ◽  
Robert Martin ◽  
Spring Zhao ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Species Differences ◽  
Free Drug ◽  
Drug Binding ◽  
Mouse Serum ◽  
Drug Levels ◽  
Ppar Agonist ◽  
Interspecies Differences

Drug binding to plasma proteins restricts their free and active concentrations, thereby affecting their pharmacokinetic properties. Species differences in plasma protein levels complicate the understanding of interspecies pharmacodynamic and toxicological effects. MBX-102 acid/JNJ39659100 is a novel PPAR- agonist in development for the treatment of type 2 diabetes. Studies were performed to evaluate plasma protein binding to MBX-102 acid and evaluate species differences in free drug levels. Equilibrium dialysis studies demonstrated that MBX-102 acid is highly bound (>98%) to human, rat and mouse albumin and that free MBX-102 acid levels are higher in rodent than in human plasma. Interspecies differences in free drug levels were further studied using PPAR- transactivation assays and a newly developed PPAR- corepressor displacement (biochemical) assay. PPAR- transactivation and corepressor displacement by MBX-102 acid was higher in rat and mouse serum than human serum. These results confirm the relevance of interspecies differences in free MBX-102 acid levels.

Species differences in the plasma protein binding of desipramine

1968 ◽  
Vol 20 (7) ◽  
pp. 571-572 ◽  
Author(s):  
Olof Borgå ◽  
Daniel L. Azarnoff ◽  
Folke Sjöqvist
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Species Differences

Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor

2005 ◽  
Vol 57 (3) ◽  
pp. 275-281 ◽  
Author(s):  
Milin R. Acharya ◽  
Alex Sparreboom ◽  
Edward A. Sausville ◽  
Barbara A. Conley ◽  
James H. Doroshow ◽  
...  
Keyword(s):  
Protein Binding ◽  
Histone Deacetylase ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Histone Deacetylase Inhibitor ◽  
Interspecies Differences ◽  
Deacetylase Inhibitor

Species differences in drug plasma protein binding

MedChemComm ◽  
2014 ◽  
Vol 5 (7) ◽  
pp. 963-967 ◽  
Author(s):  
Nicola Colclough ◽  
Linette Ruston ◽  
J. Matthew Wood ◽  
Philip A. MacFaul
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Human Plasma ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Proteins ◽  
Species Differences ◽  
Human Plasma Protein ◽  
Binding Data ◽  
Drug Plasma

Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice.

Interspecies differences in in vitro etoposide plasma protein binding

1991 ◽  
Vol 42 (11) ◽  
pp. 2246-2249 ◽  
Author(s):  
Ronald A. Fleming ◽  
Susan G. Arbuck ◽  
Clinton F. Stewart
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Interspecies Differences

Possible therapeutic interventions in COVID-19 induced ARDS by cotinine as an ACE-2 promoter and AT-1R blocker

2020 ◽  
Vol 20 ◽  
Author(s):  
Tarun Sharma ◽  
Sidharth Mehan
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Distress Syndrome ◽  
Therapeutic Interventions ◽  
Promising Candidate ◽  
Angiotensin Converting Enzyme 2 ◽  
Proinflammatory Effect ◽  
Pulmonary Permeability

: In these challenging times of the pandemic, as coronavirus disease 2019 (COVID-19) has taken over the planet, its complications such as acute respiratory distress syndrome (ARDS) have the potential to wipe out a large portion of our population. Whereas a serious lack of ventilators, vaccine being months away makes the condition even worse. That's why promising drug therapy is required. One of them was suggested in this article. It is the angiotensin-converting enzyme-2 (ACE-2) to which the COVID-19 virus binds and upon downregulation of which the pulmonary permeability increases and results in the filling of alveoli by proteinaceous fluids, which finally results in ARDS. ARDS can be assisted by angiotensinII type-1 receptor (AT-1R) blocker and ACE-2 upregulator. AT-1R blocker will prevent vasoconstriction, the proinflammatory effect seen otherwise upon its activation. ACE-2 upregulation will ensure less formation of angiotensin II, vasodilatory effects due to the formation of angiotensin (1-7), increased breakdown of bradykinin at lung level. Overall, decreased vasoconstriction of vessels supplying lungs and decreased vasodilation of lung tissues will ensure decreased pulmonary permeability and eventually relieve ARDS. It should also be considered that all components of the reninangiotensin-aldosterone system (RAAS) are located in the lung tissues. A drug with the least plasma protein binding is required to ensure its distribution across these lung tissues. Cotinine appears to be a promising candidate for COVID-19- induced ARDS. It acts across the board and acts as both an AT-1R blocker, ACE-2 upregulator. It also has a weak plasma protein binding that helps to spread through the lung tissues. In this review, we summarized that cotinine, along with COVID-19 virus replication blocker anti-virals, may prove to be a promising therapy for the treatment of COVID-19 induced ARDS.

scholarly journals Ultrafiltration Method for Plasma Protein Binding Studies and Its Limitations

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 382
Author(s):  
Camelia-Maria Toma ◽  
Silvia Imre ◽  
Camil-Eugen Vari ◽  
Daniela-Lucia Muntean ◽  
Amelia Tero-Vescan
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Specific Binding ◽  
Critical Role ◽  
Volume Ratio ◽  
Binding Studies ◽  
Experimental Conditions ◽  
Key Aspects

Plasma protein binding plays a critical role in drug therapy, being a key part in the characterization of any compound. Among other methods, this process is largely studied by ultrafiltration based on its advantages. However, the method also has some limitations that could negatively influence the experimental results. The aim of this study was to underline key aspects regarding the limitations of the ultrafiltration method, and the potential ways to overcome them. The main limitations are given by the non-specific binding of the substances, the effect of the volume ratio obtained, and the need of a rigorous control of the experimental conditions, especially pH and temperature. This review presents a variety of methods that can hypothetically reduce the limitations, and concludes that ultrafiltration remains a reliable method for the study of protein binding. However, the methodology of the study should be carefully chosen.

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