Voltammetric and electrogeneration approaches for the assessment of the oxidative drug metabolism

Abstract

In this paper, electrochemical (EC) methods have been proposed to evaluate the oxidative behavior of drugs as rapid, simple, and cheap strategies to predict some metabolic features. Various commercial drugs belonging to different therapeutic families have been assayed to deal with a wide variety of biotransformations and to cover different metabolism extents. First, differential pulse voltammetry has been applied to evaluate the oxidative behavior of drugs. Voltammetric assays have demonstrated to be highly efficient to predict the metabolism extent from the current intensity data. The second objective of this work has been the comparison of metabolite profiles from both EC and in vitro methods based on liver microsome assays. The resulting samples have been analyzed by reversed-phase liquid chromatography mode using a core-shell column and UV detection. Chromatographic methods have been established for each particular drug and its metabolites using 0.1% (v/v) formic acid aqueous solution and methanol (MeOH) as the components of the mobile phase. Drug oxidation products from both EC- and microsome-based methodologies have been compared in terms of variety and percentage from the corresponding chromatographic profiles. In general, most of the metabolites occurring in vitro have also been reproduced in the EC runs. Besides, it has been found that compositional profiles from EC experiments are dependent on experimental variables such as pH and potential. In general, acid (pH 2) and basic (pH 10) conditions and too high potentials can contribute to the generation of oxidation artifacts which differ from metabolites while milder potentials and neutral pH values may reproduce more accurately the microsome patterns. The proposed methodology is suitable for a first study of the oxidative behavior of molecules that can be related to relevant metabolic properties. The obtained information could be of great interest to prioritize or discard compounds, as a first screening, on the research of drug candidates.

Carba Analogues of Flupirtine and Retigabine with Improved Oxidation Resistance and Reduced Risk of Quinoid Metabolite Formation

“…This method has already been used to investigate the electrochemical behaviour of other oxidatively toxified drugs such as paracetamol or diclofenac [51] . Furthermore, a recent study concluded that electrochemical oxidation is a suitable approach for a preliminary investigation of the oxidative behaviour of drug candidates since the profile of generated oxidation products is roughly comparable to in vitro microsomal incubation [52] …”

“…[51] Furthermore, a recent study concluded that electrochemical oxidation is a suitable approach for a preliminary investigation of the oxidative behaviour of drug candidates since the profile of generated oxidation products is roughly comparable to in vitro microsomal incubation. [52] Figure 5 shows a representative cyclic voltammogram of compound 35 a versus retigabine. The anodic peak potentials, which are marked by dashed lines, indicate that 35 a with an oxidation potential of 633 mV is significantly more oxidationstable compared to retigabine (E p.a.…”

“…The crude residue was further purified by silica gel column chromatography (ethyl acetate/nhexane 1 : 1) to obtain 34 b as an off-white solid (1. 52…”

Metabolism‐Inspired Electrosynthesis

“…In combination with strides in developing new selective electrosynthetic methodologies that can be applied to drug molecules, this would enable a fully joined‐up approach to discovery, detection and generation of drug metabolites, and scalable synthesis of new analogues to expedite drug discovery. To achieve these grand ambitions of metabolism‐inspired electrosynthesis, further cutting‐edge development of pulse sequences for electrooxidation, engineering advantages for redox cycling and preventing electrode fouling/compound adsorption, microfluidic technologies, and rapid screening technologies are emerging and will all play a role in the wider adoption of electrosynthesis.…”

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

“…Our interest in connecting the voltammetric behaviour of drug molecules to their biological properties is derived from our research into the electrochemistry of small molecules [12][13][14] and adverse drug reactions [15,16]. Recent disparate research has found connections between the redox behaviour of a drug and its biological potency [17][18][19] and the oxidation potential and toxicity of MDMA (Ecstasy) derivatives [20,21] and thiobenzamides [22], and voltammetric studies for assessing electrogenerated drug metabolisms [23] as well as a study of xeniobiotics in the environment [24].…”