Mimicry of phase I drug metabolism – novel methods for metabolite characterization and synthesis

Abstract

The extent to which electrochemical oxidation, electrochemically assisted Fenton chemistry and synthetic metalloporphines can be used to mimic cytochrome P450 catalyzed oxidations has been investigated for a large range of metabolic reactions. Most relevant metabolic oxidations can be mimicked by at least one of the three investigated systems. The EC oxidation system successfully mimics benzylic hydroxylation, hydroxylation of aromatic rings containing electron-donating groups, N-dealkylation, S-oxidation, dehydrogenation and less efficiently N-oxidation and O-dealkylation. The EC-Fenton system is able to mimic aliphatic hydroxylation, benzylic hydroxylation, aromatic hydroxylation, N-dealkylation, N-oxidation, O-dealkylation, S-oxidation and dehydrogenation. The porphine system mimics all types of reactions although the yields are low for some reactions. In conclusion, these three complementary systems can be used during the drug discovery and development of new drugs to elucidate the structure of metabolites that are difficult to characterize in biological matrices. Moreover, such techniques can replace the classical chemistry strategy, especially when synthesis is complicated or too time-consuming in order to access metabolites for further testing.

Electrochemistry-High Resolution Mass Spectrometry to Study Oxidation Products of Trimethoprim

“…Finally, this study confirmed that electrochemical techniques are relevant not only to mimic the cytochrome P450 oxidation transformations of drugs, as has been suggested previously [10,13], but also to study the oxidation reactions of organic contaminants in wastewater treatment plants. The key role that redox reactions play in the environment make electrochemistry coupled to high resolution mass spectrometry a powerful technique to improve our understanding of the fate of EOCs in the environment.…”

“…The reactions leading to these transformation products take place within the solution. Besides being able to mimic certain reactions resulting from the metabolism of cytochrome P450 enzymes, as reported earlier [10], the electro-assisted Fenton reaction is an interesting approach to study oxidation reactions occurring during water treatment processes involving OH•.…”

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

“…Electrochemical oxidation has been found to successfully mimic CYP450 benzylic hydroxylation, hydroxylation of aromatic rings containing electron-donating groups, Ndealkylation, S-oxidation, dehydrogenation and, less efficiently, N-oxidation and Odealkylation. 24 Johansson and co-workers have demonstrated the utility of electrochemical oxidation to mimic CYP450 and liver microsome catalyzed oxidation of amodiaquine and desethylamodiaquine. 25 Other researchers have employed electrochemistry to mimic phase I oxidation of paracetamol, clozapine, trimethoprim and diclofenac.…”

Electrochemical Methods for the In Vitro Assessment of Drug Metabolism

“…The EC system successfully mimics metabolic pathways in cases where the CYP-catalyzed reactions are supposed to proceed via a mechanism initiated by one-electron oxidation, such as N-dealkylation, S-oxidation, P-oxidation, alcohol oxidation, dehydrogenation and hydroxylation of aromatic rings that contain electron-donating groups. In contrast, the CYPcatalyzed reactions initiated via direct hydrogen abstraction, such as O-dealkylation, aliphatic hydroxylation and hydroxylation of aromatic rings without electron-donating groups, generally have a very high oxidation potential for electrochemical oxidation and cannot always be mimicked using EC (Johansson et al, 2007). However, even when the EC system is not able to mimic all oxidations performed by CYP, valuable information can be obtained regarding the sensitivity of the substrate toward oxidation and the molecular position where oxidation is likely to occur.…”

“…This is the case for the electrochemically assisted Fenton reaction (EC-Fenton) that is able to mimic aliphatic hydroxylation, benzylic hydroxylation, aromatic hydroxylation, N-dealkylation, Noxidation, O-dealkylation, S-oxidation and dehydrogenation (Johansson et al, 2007). In ECFenton, the regeneration of Fe +2 is achieved by the reduction of Fe +3 at the working electrode.…”