Profiling primaquine metabolites in primary human hepatocytes using UHPLC‐QTOF‐MS with 13C stable isotope labeling

Therapeutic efficiency and hemolytic toxicity of primaquine (PQ), the only drug available for radical cure of relapsing vivax malaria are believed to be mediated by its metabolites. However, identification of these metabolites has remained a major challenge apparently due to low quantities and their reactive nature. Drug candidates labeled with stable isotopes afford convenient tools for tracking drug‐derived metabolites in complex matrices by liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS) and filtering for masses with twin peaks attributable to the label. This study was undertaken to identify metabolites of PQ from an in vitro incubation of a 1:1 w/w mixture of ¹³C₆‐PQ/PQ with primary human hepatocytes. Acquity ultra‐performance LC (UHPLC) was integrated with QTOF‐MS to combine the efficiency of separation with high sensitivity, selectivity of detection and accurate mass determination. UHPLC retention time, twin mass peaks with difference of 6 (originating from ¹³C₆‐PQ/PQ), and MS‐MS fragmentation pattern were used for phenotyping. Besides carboxy‐PQ (cPQ), formed by oxidative deamination of PQ to an aldehyde and subsequent oxidation, several other metabolites were identified: including PQ alcohol, predictably generated by oxidative deamination of PQ to an aldehyde and subsequent reduction, its acetate and the alcohol's glucuronide conjugate. Trace amounts of quinone‐imine metabolites of PQ and cPQ were also detected which may be generated by hydroxylation of the PQ/cPQ quinoline ring at the 5‐position and subsequent oxidation. These findings shed additional light on the human hepatic metabolism of PQ, and the method can be applied for identification of reactive PQ metabolites generated in vivo in preclinical and clinical studies. Copyright © 2013 John Wiley & Sons, Ltd.     

Effect of an aprotic solvent on the properties and structure of ion-exchange membranes

The effect of the aprotic solvent dimethylacetamide on the equilibrium and transport properties of heterogeneous (MK-40, MA-40, and MA-41) and homogeneous (MF-4SK) ion-exchange membranes is investigated. On the basis of concentration dependences of the conductivity and diffusion permeability of membranes, model calculations of transport-structural parameters that reflect the structural and kinetic characteristics of conducting phases of the swollen polymer are performed. The effect of the aprotic solvent on the flow of current through the structural fragments of the ion-exchange material is estimated. The causes of changes that are induced in the properties of the membranes by the aprotic solvent are ascertained.     

Thermodynamic Equilibrium between an Ionite's Gel Part and a Simple-Salt Solution with Allowance for Water Dissociation

When solving an ion-exchange equilibrium problem it is usually taken into account that the ionite, according to a two-phased model, comprises microphases of a gel and an equilibrium solution. The question of equilibrium in this case involves the necessity to take into account not only ions of salt contained in an aqueous solution, but ions of hydrogen and hydroxyl, which emerge in the water dissociation process, as well. Setting up such a problem is dictated, for example, by the application of electrodialysis for the production of deeply-desalinated water. In the work, for a solution of a simple salt, relations are established, which allow one to compute complete ionic composition of phases of solution and gel on the basis of specified values of concentrations of cations and anions of salt in solution.     

Overlimiting Electrodiffusion Transport in the Diffusion Layer as a Function of Rate Constants of Dissociation and Recombination of Water: A Numerical Calculation

A boundary-value problem, which permits discovering the effect the rate constants of dissociation and recombination of water have on the electrical and mass transfer in a diffusion layer at the ion-exchange membrane/solution interface in an overlimiting mode, is solved numerically. According to the calculation, the only value of the rate constant for reactions of dissociation and recombination of pure water determined experimentally and reported in the literature is underrated by several orders of magnitude.     

Modeling Transport Asymmetry in Bilayered Ion-Exchange Membranes Interacting with Surface-Active Organic Substances

A model is suggested for the electrical mass transfer in bilayered ion-exchange membranes, which accounts for the layers' structure. The concentration polarization in a bilayered system is analyzed and the extreme concentration variations at the boundary between layers with different selectivities are determined. It is shown that the current characteristics and the diffusion penetrability can go asymmetric following a change in the orientation of a bilayered membrane with respect to the ion flow. The asymmetry of an integral diffusion penetrability coefficient is determined quantitatively for ion-exchange membranes modified with surface-active organic substances. It is shown that the proposed approach is adequate for describing transport phenomena in anisotropic membranes with stable layer characteristics.     

Characterization of ion-exchange membrane materials: properties vs structure

This review focuses on the preparation, structure and applications of ion-exchange membranes formed from various materials and exhibiting various functions (electrodialytic, perfluorinated sulphocation-exchange and novel laboratory-tested membranes). A number of experimental techniques for measuring electrotransport properties as well as the general procedure for membrane testing are also described. The review emphasizes the relationships between membrane structures, physical and chemical properties and mechanisms of electrochemical processes that occur in charged membrane materials. The water content in membranes is considered to be a key factor in the ion and water transfer and in polarization processes in electromembrane systems. We suggest the theoretical approach, which makes it possible to model and characterize the electrochemical properties of heterogeneous membranes using several transport-structural parameters. These parameters are extracted from the experimental dependences of specific electroconductivity and diffusion permeability on concentration. The review covers the most significant experimental and theoretical research on ion-exchange membranes that have been carried out in the Membrane Materials Laboratory of the Kuban State University. These results have been discussed at the conferences "Membrane Electrochemistry", Krasnodar, Russia for many years and were published mainly in Russian scientific sources.     

The conjugation of ionic flows in the diffusion layers of electrodialysis systems

Fundamental regularities of the ion interference in diffusion layers of electrodialysis systems are revealed, as well as their effect on the electrical field strength, through which the ionic flows in their turn affect each other.     

The three-wire model and Lichtenecker’s equation for calculations of the conductivity of ion-exchange columns

The approaches to the evaluation of the conductivity of ion-exchange columns are analyzed. Specifically, the three-wire model and Lichtenecker’s power equation are examined. The problem of how the coefficient of ion-exchange column filling and the parameter characterizing the state of conducting phases with respect to the current flow are related to the parameters involved in the equations of the three-wire model is treated theoretically. The common points and the coincident portions of the functions obtained in each of the approaches and some discrepancies between the functions are found. The discrepancies are determined by the special features of the models under consideration. Original Russian Text ? N.P. Gnusin, N.P. Berezina, N.A. Kononenko, O.A. Demina, L.A. Annikova, 2009, published in Zhurnal Fizicheskoi Khimii, 2009, Vol. 83, No. 1, pp. 122–126.     

Diffusion of acid and alkaline salt solutions through the Nernst diffusion layer

The behavior of diffusion layer under the conditions of salt transfer with excess of acid or alkali, involving the hydrogen and hydroxyl ions, is studied. The transfer is affected by the applying of current. The method of investigation was mathematical simulation based on the solving of boundary problems by using the Nernst-Planck equation with regard to the corresponding conditions of the transfer.     

Method of model parameter calculation of ion-exchange resins

Russian Journal of Electrochemistry - A method for determination of parameters of a three-wire model and Lichtenecker model on the basis of experimental data of conductivity measurement for...