title: Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance.
abstract: Variable pharmacokinetics of high-dose-methotrexate (MTX) is responsible for severe toxicities. Unpredictable overexposure still occurs during some courses despite having controlled the main factors known to play a role in its elimination. The aim of our study was to evaluate whether the urine metabolomic profile measured at the time of MTX administration is predictive of the drug's clearance and/or of treatment-related toxicity. We analyzed the urine content of endogenous metabolites before MTX administration in a cohort of adult patients treated for lymphoid malignancies. Individual MTX clearance (MTXCL) was estimated from population pharmacokinetic analyses of therapeutic drug monitoring data. We determined the urine metabolite content by gas chromatography-mass spectrometry (GC-MS) and applied Partial Least Square (PLS) analysis to assess the relationship between the urine metabolome and MTXCL. External validation was applied to evaluate the performances of the PLS model. We used orthogonal partial least squares discriminant analysis (OPLS-DA) to distinguish patients with normal or delayed elimination, and patients with or without toxicity. Sixty-two patients were studied. We obtained a very good prediction of individual MTX clearance using a set of 28 metabolites present in patient urine at baseline. The mean prediction error and precision were -0.36% and 21.4%, respectively, for patients not included in the model. The model included a set of endogenous organic anions, of which the tubular secretion depends on organic anion transporter (OAT) function. Our analyses did not allow us to discriminate between patients with or without delayed elimination or those who did or did not experience toxicity. Urinary metabolomics can be informative about an individual's ability to clear MTX. More broadly, it paves the way for the development of a biomarker of tubular secretion, easily measurable from endogenous substances.
authors.affiliation: EA4245 "Cellules Dendritiques, Immuno-Intervention et Greffes", Université François Rabelais, Faculté de Médecine, Bâtiment Vialle, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France. Electronic address: kienana.muhrez@etu.univ-tours.fr.
authors.forename: Kienana
authors.initials: K
authors.lastname: Muhrez
authors.affiliation: EA4245 "Cellules Dendritiques, Immuno-Intervention et Greffes", Université François Rabelais, Faculté de Médecine, Bâtiment Vialle, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France; Laboratoire de Biochimie et Biologie Moléculaire, CHU Bretonneau, 2 bis Boulevard Tonnellé, 37044 Tours, France. Electronic address: isabelle.benz-debretagne@univ-tours.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Benz-de Bretagne
authors.affiliation: Equipe Neurogénétique et Neurométabolomique, INSERM U930, Université François Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37044 Tours Cedex 9, France; Département d'Analyse Chimique Biologique et Médicale. Plateforme Scientifique et Technique-Analyse des Systèmes Biologiques (PST-ASB), Université François-Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France. Electronic address: lydie.nadal@univ-tours.fr.
authors.forename: Lydie
authors.initials: L
authors.lastname: Nadal-Desbarats
authors.affiliation: Equipe Neurogénétique et Neurométabolomique, INSERM U930, Université François Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37044 Tours Cedex 9, France. Electronic address: helene.blasco@univ-tours.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
authors.affiliation: Service d'Hématologie, CHU Bretonneau, 2 bis Boulevard Tonnellé, 37044 Tours, France. Electronic address: emmanuel.gyan@univ-tours.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.affiliation: Service d'Hématologie, Hôpital Pitié-Salpétrière, APHP, Boulevard de l'Hôpital, 75014 Paris, France. Electronic address: sylvain.choquet@psl.aphp.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
authors.affiliation: Département d'Analyse Chimique Biologique et Médicale. Plateforme Scientifique et Technique-Analyse des Systèmes Biologiques (PST-ASB), Université François-Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France. Electronic address: frederic.montigny@univ-tours.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Montigny
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, CHU Bretonneau, 2 bis Boulevard Tonnellé, 37044 Tours, France; Equipe Neurogénétique et Neurométabolomique, INSERM U930, Université François Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37044 Tours Cedex 9, France; Département d'Analyse Chimique Biologique et Médicale. Plateforme Scientifique et Technique-Analyse des Systèmes Biologiques (PST-ASB), Université François-Rabelais, Faculté de Médecine, Bâtiment Bretonneau, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France. Electronic address: emond@univ-tours.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.affiliation: EA4245 "Cellules Dendritiques, Immuno-Intervention et Greffes", Université François Rabelais, Faculté de Médecine, Bâtiment Vialle, 10 Boulevard Tonnellé, 37032 Tours Cedex 1, France; Laboratoire de Biochimie et Biologie Moléculaire, CHU Bretonneau, 2 bis Boulevard Tonnellé, 37044 Tours, France. Electronic address: chantal.barin-leguellec@univ-tours.fr.
authors.forename: Chantal
authors.initials: C
authors.lastname: Barin-Le Guellec
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000493:pharmacokinetics*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000502:physiology*
chemical_list: D027361:Organic Anion Transporters; D008727:Methotrexate
keywords: Endogenous metabolites; Metabolomics; Methotrexate; Organic anion transporters (OATs); Pharmacometabolomics; Renal secretion; Tubular secretion