title: Chiral analysis of carvedilol and its metabolites hydroxyphenyl carvedilol and O-desmethyl carvedilol in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical pharmacokinetic study.
abstract: Carvedilol is an antihypertensive drug, which is available in clinical practice as a racemic mixture. (S)-(-)-carvedilol is a β- and α1-adrenergic antagonist, while (R)-(+)-carvedilol only acts as an α1-adrenergic antagonist. Carvedilol is metabolized mainly by glucuronidation and, to a lesser extent, by CYP2D6 to hydroxyphenyl carvedilol (OHC) and by CYP2C9 to O-desmethyl carvedilol (DMC). This study describes the development and validation of a method for the sequential analysis of the enantiomers of carvedilol, OHC and DMC in plasma using a Chirobiotic(®) V chiral-phase column coupled to an LC-MS/MS system. The method was linear in the range of 0.05-100, 0.05-10 and 0.02-10 ng/mL for the carvedilol, OHC and DMC enantiomers, respectively. Application of the method to the investigation of a patient with type 2 diabetes mellitus treated with a single oral dose of 25mg racemic carvedilol showed plasma accumulation of the (R)-(+)-carvedilol, (R)-(+)-DMC and (R)-(+)-OHC enantiomers. These results suggest that plasma accumulation of (R)-(+)-carvedilol cannot be explained by its oxidative metabolism.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Glauco Henrique Balthazar
authors.initials: GHB
authors.lastname: Nardotto
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: lanchote@fcfrp.usp.br.
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D002227:Carbazoles / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000077261:Carvedilol; D002853:Chromatography, Liquid / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D011412:Propanolamines / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol
keywords: Carvedilol; Diabetes; Enantiomers; Metabolism; Pharmacokinetics; Plasma