title: Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling.
abstract: BACKGROUND
  Glucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy is hampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance. Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone but reduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers, which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim to provide the first description of the metabolic perturbations induced by acute and therapeutic treatments with prednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-induced metabolic effects.
  
  
  METHODS
  A randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthy men. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg (n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mg prednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) and after prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles.
  
  
  RESULTS
  At day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urine and serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation of glucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives at day 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels of proteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with the homeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulin resistance.
  
  
  CONCLUSIONS
  This study provides evidence that urinary metabolomics represents a noninvasive way of monitoring the effect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers of glucocorticoid-induced insulin resistance. It might, therefore, help the development of improved synthetic glucocorticoids.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00971724.
authors.affiliation: Division Analytical Biosciences, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands ; MSD, Molenstraat 110, 5340 BH Oss, The Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ellero-Simatos
authors.affiliation: Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.affiliation: MSD, Molenstraat 110, 5340 BH Oss, The Netherlands ; TNO, Zeist, the Netherlands.
authors.forename: Ton
authors.initials: T
authors.lastname: Rullmann
authors.affiliation: MSD, Molenstraat 110, 5340 BH Oss, The Netherlands ; Synthon, Nijmegen, The Netherlands.
authors.forename: Wim Ha
authors.initials: WH
authors.lastname: Dokter
authors.affiliation: Division Analytical Biosciences, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors.forename: Raymond
authors.initials: R
authors.lastname: Ramaker
authors.affiliation: Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.affiliation: Xendo, Groningen, The Netherlands ; PRA, Early Development Services, Zuidlaren, The Netherlands.
authors.forename: Thijs Mp
authors.initials: TM
authors.lastname: van Iersel
authors.affiliation: Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Age K
authors.initials: AK
authors.lastname: Smilde
authors.affiliation: Division Analytical Biosciences, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333CC Leiden, The Netherlands ; Netherlands Metabolomics Centre, Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankemeier
authors.affiliation: MSD, Molenstraat 110, 5340 BH Oss, The Netherlands ; NIZO food research BV, Health Division, Ede, The Netherlands.
authors.forename: Wynand
authors.initials: W
authors.lastname: Alkema