title: P450-catalyzed vs. electrochemical oxidation of haloperidol studied by ultra-performance liquid chromatography/electrospray ionization mass spectrometry.
abstract: The metabolites formed via the major metabolic pathways of haloperidol in liver microsomes, N-dealkylation and ring oxidation to the pyridinium species, were produced by electrochemical oxidation and characterized by ultra-performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS). Liver microsomal incubations and electrochemical oxidation in the presence of potassium cyanide (KCN) resulted in two diastereomeric cyano adducts, proposed to be generated from trapping of the endocyclic iminium species of haloperidol. Electrochemical oxidation of haloperidol in the presence of KCN gave a third isomeric cyano adduct, resulting from trapping of the exocyclic iminium species of haloperidol. In the electrochemical experiments, addition of KCN almost completely blocked the formation of the major oxidation products, namely the N-dealkylated products, the pyridinium species and a putative lactam. This major shift in product formation by electrochemical oxidation was not observed for the liver microsomal incubations where the N-dealkylation and the pyridinium species were the major metabolites also in the presence of KCN. The previously not observed dihydropyridinium species of haloperidol was detected in the samples, both from electrochemical oxidation and the liver microsomal incubations, in the presence of KCN. The presence of the dihydropyridinium species and the absence of the corresponding cyano adduct lead to the speculation that an unstable cyano adduct was formed, but that cyanide was eliminated to regenerate the stable conjugated system. The formation of the exocyclic cyano adduct in the electrochemical experiments but not in the liver microsomal incubations suggests that the exocyclic iminium intermediate, obligatory in the electrochemically mediated N-dealkylation, may not be formed in the P450-catalyzed reaction.
authors.affiliation: Discovery DMPK, AstraZeneca R&D Mölndal, Sweden. tove.johansson.malin@astrazeneca.com
authors.forename: Tove Johansson
authors.initials: TJ
authors.lastname: Mali'n
authors.forename: Lars
authors.initials: L
authors.lastname: Weidolf
authors.forename: Neal
authors.initials: N
authors.lastname: Castagnoli
authors.forename: Ulrik
authors.initials: U
authors.lastname: Jurva
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D055664:Electrochemical Techniques / Q000379:methods*; D006220:Haloperidol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011190:Potassium Cyanide / Q000737:chemistry; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D014150:Antipsychotic Agents; D003577:Cytochrome P-450 Enzyme System; D006220:Haloperidol; D011190:Potassium Cyanide