Disproportionation of clozapine radical: a link between one-electron oxidation of clozapine and formation of its nitrenium cation.
The primary products of one-electron oxidation of clozapine and olanzapine, very effective atypical antipsychotic drugs, have been spectroscopically characterized. The oxidation process has been studied under glassy matrix conditions and by a pulse radiolysis technique in aqueous solution. The rate constants for the oxidation of clozapine with dibromide radical anion ( k = 2 x 10 (9) M (-1) s (-1)) and azide radical ( k = 2.3 x 10 (9) M (-1) s (-1)) in aqueous solution were measured. The computational DFT results support the identification of the transient species. The mechanistic aspects of reactivity of radical cations, radicals, and nitrenium cations have been investigated. A disproportionation reaction ( k > or = 1 x 10 (8) M (-1) s (-1)) was proposed as a link between the products of one-electron oxidation and formation of the nitrenium cations of clozapine and olanzapine, products likely responsible for the pathogenesis of adverse drug reactions. The rate constants for the reactions of nitrenium cation of clozapine with glutathione ( k = 3.4 x 10 (4) M (-1) s (-1)) and cysteine ( k = 9.8 x 10 (4) M (-1) s (-1)) were determined.
Sikora
Adam
A
Institute of Applied Radiation Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland.
Adamus
Jan
J
Marcinek
Andrzej
A
D000465:Algorithms; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry; D001569:Benzodiazepines / Q000737:chemistry; D001965:Bromides / Q000737:chemistry; D002412:Cations; D003024:Clozapine / Q000737:chemistry*; D004583:Electrons; D005609:Free Radicals / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009584:Nitrogen / Q000737:chemistry*; D000077152:Olanzapine; D010084:Oxidation-Reduction; D011675:Pulse Radiolysis; D013057:Spectrum Analysis
D014150:Antipsychotic Agents; D001386:Azides; D001965:Bromides; D002412:Cations; D005609:Free Radicals; D001569:Benzodiazepines; D005978:Glutathione; D003024:Clozapine; D009584:Nitrogen; D000077152:Olanzapine