title: Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.
abstract: Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans, a technique of detection that shows comparable selectivity and sensitivity to ion transitions (SRM) performed with triple-quadrupole (TQ)-MS but that allows de facto determination of "all" ions including drug metabolites. This could be of potential utility in in vivo drug metabolism and pharmacovigilance studies in order to have a more comprehensive insight in drug biotransformation profile differences in patients. This simultaneous quantitative and qualitative (Quan/Qual) approach has been tested with 20 patients chronically treated with tamoxifen (TAM). The absolute quantification of TAM and three metabolites in plasma was realized using HR- and TQ-MS and compared. The same LC-HR-MS analysis allowed the identification and relative quantification of 37 additional TAM metabolites. A number of new metabolites were detected in patients' plasma including metabolites identified as didemethyl-trihydroxy-TAM-glucoside and didemethyl-tetrahydroxy-TAM-glucoside conjugates corresponding to TAM with six and seven biotransformation steps, respectively. Multivariate analysis allowed relevant patterns of metabolites and ratios to be associated with TAM administration and CYP2D6 genotype. Two hydroxylated metabolites, α-OH-TAM and 4'-OH-TAM, were newly identified as putative CYP2D6 substrates. The relative quantification was precise (<20 %), and the semiquantitative estimation suggests that metabolite levels are non-negligible. Metabolites could play an important role in drug toxicity, but their impact on drug-related side effects has been partially neglected due to the tremendous effort needed with previous MS technologies. Using present HR-MS, this situation should evolve with the straightforward determination of drug metabolites, enlarging the possibilities in studying inter- and intra-patients drug metabolism variability and related effects.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, 1211, Geneva 4, Switzerland.
authors.forename: Elyes
authors.initials: E
authors.lastname: Dahmane
authors.forename: Julien
authors.initials: J
authors.lastname: Boccard
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Serge
authors.initials: S
authors.lastname: Rudaz
authors.forename: Laurent
authors.initials: L
authors.lastname: Décosterd
authors.forename: Eric
authors.initials: E
authors.lastname: Genin
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duretz
authors.forename: Maciej
authors.initials: M
authors.lastname: Bromirski
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
authors.forename: Bertrand
authors.initials: B
authors.lastname: Rochat
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D015394:Molecular Structure; D010601:Pharmacology, Clinical; D013629:Tamoxifen / Q000097:blood* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen