The impact of plasma protein binding on toxic plasma drug concentration

2016 ◽  
Vol 9 (4) ◽  
pp. 345
Author(s):  
Andreas Svennebring
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Drug Concentration ◽  
Plasma Drug Concentration ◽  
Plasma Drug ◽  
The Impact

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

2005 ◽  
Vol 316 (1) ◽  
pp. 349-355 ◽  
Author(s):  
Daniel A. J. Bow ◽  
Jennifer L. Perry ◽  
John D. Simon ◽  
John B. Pritchard
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Organic Anions ◽  
Renal Transport ◽  
The Impact

scholarly journals Combinatorial Approaches to Overcome Plasma Protein Inhibition of FLT3 Tyrosine Kinase Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1362-1362
Author(s):  
David J Young ◽  
Jun O Liu ◽  
Donald Small
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Parent Compound ◽  
Dependent Cell ◽  
The Impact

Abstract Background: The FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML) and also results in poor prognosis for adult and pediatric patients, and thus represents an attractive target for tyrosine kinase inhibitors (TKI). The activity of FLT3-targeted TKI is inhibited to varying extents by plasma protein binding. Staurosporine (STS)-derived TKI are inhibited almost exclusively by the plasma protein alpha-1 acid glycoprotein (AGP), an acute-phase reactant. We studied the impact of AGP binding on the other STS-derivatives and report the development of a novel method to overcome this binding. Methods: We assayed the impact of human AGP upon the activity of the STS-derived TKI (midostaurin, lestaurtinib, TTT-3002) against proliferation of the FLT3-ITD dependent cell line MOLM-14 and upon the parent compound (staurosporine) against the non-FLT3-dependent cell line HL-60. These experiments were repeated, co-incubating with drugs that competitively bind AGP to identify those that may restore TKI activity. Results: The TKI are inhibited in a linear AGP-dependent manner (fold change increase of IC50 per mg/dL AGP: midostaurin 3.00-fold, lestaurtinib 11.73-fold, TTT-3002 0.33-fold) across the range of AGP concentrations observed in human plasma. These results correspond to the drug-protein binding constants for the TKI: midostaurin 12.6 µM-1, lestaurtinib 49.2 µM-1, TTT-3002 1.41 µM-1, all validated by competitive fluorescence displacement of the AGP-binding dye, 1-anilino-8-naphthalenesulfonate. These results predict that in vivo IC50 values for these FLT3 TKI will be significantly higher than those measured under typical (10% FCS) in vitro culture conditions: midostaurin 4.7 µM, lestaurtinib 4.8 µM, TTT-3002 34 nM. By comparison, activity of the parent compound, staurosporine, against HL60 is completely inhibited by AGP. Assays using bovine plasma, serum or purified AGP do not demonstrate similar inhibition of FLT3 TKI. We are developing a murine model to overcome this experimental limitation. We have developed a mathematical model describing the interactions of AGP with FLT3 TKI using classical mass action relationships that match experimental results and furthermore describe the effects of competitive plasma protein binding by unrelated agents. These models predict that disinhibition of TKI may be achievable in vivo, and define the properties of such "rescue" agents. Mifepristone binds AGP (2-10 fold greater than STS-derived TKI) and has no independent effect upon FLT3-dependent cell growth. Co-treatment with mifepristone restores the IC50 of TTT-3002 from 12 nM with AGP to < 0.1 nM. Disinhibition is seen for lestaurtinib (IC50 shift reduced from >1000-fold to 50-fold) and midostaurin (300-fold reduced to 80-fold). This results in predicted in vivo IC50 that are clinically relevant, and serve as a proof-of-principle for this method. Using this principle we have screened a library of FDA-approved compounds for the ability to rescue TKI activity despite the presence of potentially inhibitory plasma proteins. This screen has identified 40 potential agents that may displace STS-derived TKI from AGP, and an additional 90 agents that may restore TKI activity through off-target effects. Several agents have already been validated in vitro, and found to decrease the IC50 of midostaurin and other TKI to clinically achievable ranges despite the presence of inhibiting proteins. Conclusions: The failure of FLT3 TKI in previous clinical trials has been linked to a lack of plasma drug activity. This work provides biochemical confirmation of this effect. Furthermore, these results indicate that this is a property of the class as a whole, including midostaurin. Indeed, for midostaurin, the predicted in vivo IC50 is higher than steady state levels suggesting that in clinical trials it likely acts through non-FLT3 mechanisms. Disinhibition of TKIs by mifepristone suggests a novel combinatorial approach restore TKI activity using unrelated compounds. We are currently examining other agents for similar synergy. By improving TKI potency in the face of inhibitory plasma protein binding, such combinations would be expected to improve their clinical efficacy by reducing the dosages necessary to thoroughly inhibit FLT3. Finally, this report provides a method for predicting at least one factor that affects the success or failure of FLT3 TKI in clinical trials. Disclosures No relevant conflicts of interest to declare.

The impact of plasma protein binding on the tissue distribution of warfarin - investigation in nagase analbuminemic rats (NAR)

2019 ◽  
Vol 34 (1) ◽  
pp. S37
Author(s):  
Jodie Pang ◽  
John Chen ◽  
Katherine Cunico ◽  
Jose Imperio ◽  
Jae Chang ◽  
...  
Keyword(s):  
Protein Binding ◽  
Tissue Distribution ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
The Impact

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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