Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance. (April 2017)

• Record Type: Journal Article
• Authors: Muhrez, Kienana; Benz-de Bretagne, Isabelle; Nadal-Desbarats, Lydie; Blasco, Hélène; Gyan, Emmanuel; Choquet, Sylvain; Montigny, Frédéric; Emond, Patrick; Barin-Le Guellec, Chantal
• Is Part Of: Pharmacological research. Volume 118(2017:Apr.)
• Page Start: 121
• Page End: 132
• Publication Date: 2017-04
• Subjects: MTX methotrexate -- HD-MTX high-dose methotrexate -- OH-MTX hydroxymethotrexate -- UCP (I/I + III) ratio urinary coproporphyrin ratio -- MRP2 multidrug resistance related protein-2 -- TDM therapeutic drug monitoring -- POP-PK population pharmacokinetics -- H24 24 h after the start of MTX infusion -- Hx x h after the start of MTX infusion -- CTCAE common terminology criteria for adverse events v.4.03 -- NONMEM nonlinear mixed effect modeling program -- GC–MS gas chromatography–mass spectrum -- BSTFA N, O-bis(trimethylsilyl)trifluoroacetamide -- EI electronic impact -- QC quality control -- PCA principal component analysis -- UV unit variance -- DModX distance to the model plane -- MTXCL clearance of methotrexate -- VIP variable importance on projection -- CV-ANOVA ANOVA of the cross-validated residuals -- RMSE-CV root mean square error from cross-validation -- RMSE-P root mean square error of prediction -- ME mean error -- PE prediction error -- RMSE root mean squares error -- OPLS-DA orthogonal projections to latent structures discriminant analysis -- ROC receiver operating characteristic -- OATs organic anion transporters; Methotrexate -- Organic anion transporters (OATs) -- Endogenous metabolites -- Tubular secretion -- Metabolomics -- Pharmacometabolomics -- Renal secretion; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.05.021
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.