Mimicry of phase I drug metabolism--novel methods for metabolite characterization and synthesis.
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.
Johansson
Tove
T
Discovery DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, SE-421 83 Mölndal, Sweden.
Weidolf
Lars
L
Jurva
Ulrik
U
D032701:Biomimetics / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004563:Electrochemistry / Q000379:methods*; D006801:Humans; D008790:Metoprolol / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
D003577:Cytochrome P-450 Enzyme System; D008790:Metoprolol