Effect of Altered Plasma Protein Binding on Apparent Volume of Distribution

1979 ◽  
Vol 68 (9) ◽  
pp. 1203-1205 ◽  
Author(s):  
Svein Øie ◽  
Thomas N. Tozer
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Apparent Volume Of Distribution

Cremophor EL Alters the Plasma Protein Binding and Pharmacokinetic Profile of Valspodar in Rats

Drug Research ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 591-595
Author(s):  
Ziyad Binkhathlan
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Pharmaceutical Formulations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Cremophor El ◽  
Unbound Fraction ◽  
Peg 400

AbstractCremophor EL is a nonionic surfactant widely used in pharmaceutical formulations. Nonetheless, there are several reports on the influence of this excipient on the protein binding, pharmacokinetics, and pharmacodynamics of drugs. Valspodar is an investigational non-immunosuppressive derivative of cyclosporine A, used in clinical trials for treatment of multidrug resistant tumors. The formulation of valspodar (Amdray®) contains cremophor EL and ethanol as solubilizing agents. The main aim of the current study was to assess the plasma protein binding (in vitro) and the pharmacokinetic profile of valspodar in the cremophor EL-based formulation in comparison to a cremophor EL-free formulation following intravenous (i. v.) administration to rats. Valspodar dissolved in PEG 400/ethanol (diluted in Dextrose 5%) was used as the cremophor EL-free formulation. The in vitro plasma unbound fraction (f u) of valspodar in the cremophor EL formulation was 2.3-fold higher than the PEG 400/ethanol formulation. Following a single i. v. dose of 5 mg/kg, valspodar in the cremophor EL-based formulation had around 50% lower plasma AUC compared to the PEG 400/ethanol formulation. Moreover, the cremophor EL formulation had significantly higher volume of distribution and clearance in comparison to the PEG 400-based formulation. The results highlight the significance of excipient-drug interaction that should not be overlooked during the early stages of drug development.

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.

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