HPLC-UV ATMOSPHERIC-PRESSURE IONIZATION MASS-SPECTROMETRIC DETERMINATION OF THE DOPAMINE-D2 AGONIST N-0923 AND ITS MAJOR METABOLITES AFTER OXIDATIVE-METABOLISM BY RAT-LIVER, MONKEY LIVER, AND HUMAN LIVER-MICROSOMES

PJ SWART, GM BRONNER, AP BRUINS, K ENSING, PG TEPPER, RA DEZEEUW

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Abstract

An innovative custom-built atmospheric ionization source afforded an opportunity to perform on-line LC/MS analysis and to obtain identification of metabolites without need to rely on radioactive profiling. An HPLC with a UV detector coupled to a modified R 3010 triple quadrupole mass spectrometer was used in which nitrogen gas effectively prevented the clustering of ions with polar solvent molecules as well as acting as the nebulizing gas for the ionspray LC/MS interface. This approach was useful in elucidating the oxidative metabolism of the potent dopamine D2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rat-, monkey-, and human liver microsome preparations. Microsomes from monkey showed the highest metabolic activity, with 8.3 nmol . min-1 . mg-1 protein; the human material resulted in the lowest, 1.2 nmol . min-1 . mg-1 protein. Metabolic profiling showed that the three species produced the same metabolites, but to different extents. Liver microsomes metabolized the (-) enantiomer to 2-(N-2-thienylethylamino)-5-hydroxytetralin, 2-(N-propylamino)-5-hydroxytetralin, and 2-(N-propyl-N-2-thienylethylamino)-5,6-dihydroxytetralin, a catechol metabolite. Due to the weak dopaminergic affinities of the N-dealkylated compounds and the high metabolic conversion of the catechol, no therapeutic effects of these compounds may be expected in vivo.

Original languageEnglish
Pages (from-to)279-290
Number of pages12
JournalToxicology methods
Volume3
Issue number4
Publication statusPublished - Dec-1993

Keywords

  • IONIZATION
  • ANALYSIS, LC MS
  • HPLC
  • AGONIST, DOPAMINE-D2
  • ORAL BIOAVAILABILITY
  • RECEPTOR AGONIST
  • N-0437
  • 2-(N-PROPYL-N-2-THIENYLETHYLAMINO)-5-HYDROXYTETRALIN
  • DISPOSITION
  • INVITRO
  • SYSTEMS
  • FATE

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