Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK′ = 5.8–6.0), while its binding to HSA is much weaker (logK′ ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and ‘acute-phase’ conditions as well

In vitro biodistribution studies on clinically approved FGFR inhibitors ponatinib, nintedanib, erlotinib and the investigational inhibitor KP2692

Binding towards human serum albumin (HSA) and α1-acid glycoprotein (AGP) of three approved fibroblast growth factor receptor (FGFR) inhibitors ponatinib (PON), nintedanib (NIN) and erdafitinib (ERD), as well as the experimental drug KP2692 was studied by means of spectrofluorometric and UV-visible spectrophotometric methods. Additionally, proton dissociation processes, lipophilicity, and fluorescence properties of these four molecules were investigated in detail

Speciation of metal complexes of medicinal interest: relationship between solution equilibria and pharmaceutical properties

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids

Interaction of folic acid and some matrix metalloproteinase (MMP) inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin

Human serum albumin binding of folic acid and its γ-hydroxamate/ carboxylate derivatives was studied by ultrafiltration and spectrofluorimetry, and it was found that the ligands exhibit a moderate binding (KD ∼ 2-50 μM), and the folate-γ-phenylalanine represents the highest conditional binding constant towards albumin. This feature may have importance in the serum transport processes of these ligands. Interaction of folic acid and its derivatives with Zn(II) was investigated in aqueous solution to obtain the composition and stabilities of the complexes by the means of pH-potentiometry, 1H NMR and electrospray ionization mass spectrometry, together with the characterization of the proton dissociation processes and the hydro-lipophilic properties of the ligands. The formation of mono-ligand complexes was demonstrated in all cases and the contribution of the glutamyl carboxylates to the coordination was excluded. Binding of folic acid and its γ-carboxylate derivatives to Zn(II) via the pteridine moiety is suggested, while the (O,O) coordination fashion of the folate-γ-hydroxamate ligands has importance in their inhibitory activity against Zn(II)-containing matrix metalloproteinases. It was found that the enzyme inhibition of these folate-γ-hydroxamate ligands is mainly tuned by other features, such as the lipophilic character rather than the Zn(II)-chelate stability. © 2010 Elsevier Inc. All rights reserved

Fluorescence Quenching of Tyrosine-Ag Nanoclusters by Metal Ions: Analytical and Physicochemical Assessment

A new synthesis method is described for the first time to produce silver nanoclusters (AgNCs) by using the tyrosine (Tyr) amino acid. Several important parameters (e.g., molar ratios, initial pH, reaction time etc.) were optimized to reach the highest yield. The formed Tyr-AgNCs show characteristic blue emission at λem = 410 nm, and two dominant fluorescence lifetime components were deconvoluted (τ1 ~ 3.7 and τ2 ~ 4.9 ns). The NCs contained metallic cores stabilized by dityrosine. For possible application, the interactions with several metal ions from the tap water and wastewater were investigated. Among the studied cations, four different ions (Cu2+, Ni2+, Fe3+, and Rh3+) had a dominant effect on the fluorescence of NCs. Based on the detected quenching processes, the limit of detection of the metal ions was determined. Static quenching (formation of a non-luminescent complex) was observed in all cases by temperature-dependent measurements. The calculated thermodynamic parameters showed that the interactions are spontaneous ranked in the following order of strength: Cu2+ > Fe3+ > Rh3+ > Ni2+. Based on the sign and relations of the standard enthalpy (ΔH°) and entropy changes (ΔS°), the dominant forces were also identified