title: Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome P450-catalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry.
abstract: A comparative study of the electrochemical conversion and the biotransformation performed by the cytochrome P450 (CYP450) obtained by rat liver microsomes has been achieved to elucidate the oxidation mechanism of both acebutolol and alprenolol. For this purpose, a wide range of reactions such as N-dealkylation, O-dealkoxylation, aromatic hydroxylation, benzyl hydroxylation, alkyl hydroxylation, and aromatic hydroxylation have been examined in this study, and their mechanisms have been compared. Most of the results of the electrochemical oxidation have been found to be in accordance with those obtained by incubating acebutolol and alprenolol in the presence of CYP450, i.e., N-dealkylation, benzyl hydroxylation, and O-dealkoxylation reactions catalyzed by liver microsomes were found to be predicted by the electrochemical oxidation. The difficulty for the electrochemical process to mimic both aromatic and alkyl hydroxylation reactions has also been discussed, and the hypothesis for the absence of aromatic hydroxylated and alkyl hydroxylated products, respectively, for alprenolol and acebutolol, under the anodic oxidation has been supported by theoretical calculation. The present study highlights the potential and limitation of coupling of electrochemistry-liquid chromatography-high-resolution mass spectrometry for the study of phase I and phase II reactions of acebutolol and alprenolol.
authors.affiliation: LUNAM Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, 2 rue de la Houssinière, BP 92208, 44322, Nantes cedex 3, France.
authors.forename: Ugo
authors.initials: U
authors.lastname: Bussy
authors.forename: Marcel
authors.initials: M
authors.lastname: Delaforge
authors.forename: Chaimaâ
authors.initials: C
authors.lastname: El-Bekkali
authors.forename: Véronique
authors.initials: V
authors.lastname: Ferchaud-Roucher
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Illa
authors.initials: I
authors.lastname: Tea
authors.forename: Nicolas
authors.initials: N
authors.lastname: Galland
authors.forename: Denis
authors.initials: D
authors.lastname: Jacquemin
authors.forename: Mohammed
authors.initials: M
authors.lastname: Boujtita
mesh_terms: D000070:Acebutolol / Q000378:metabolism* / Q000493:pharmacokinetics; D000526:Alprenolol / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D002384:Catalysis; D002853:Chromatography, Liquid / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D055664:Electrochemical Techniques; D006900:Hydroxylation; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000378:metabolism; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D051381:Rats
chemical_list: D000070:Acebutolol; D000526:Alprenolol; D003577:Cytochrome P-450 Enzyme System