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

An innovative custom-built atmospheric ionization source afforded an o pportunity to perform on-line LC/MS analysis and to obtain identificat ion of metabolites without need to rely on radioactive profiling. An H PLC 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 dopa mine D2 agonist (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 . m in-1 . mg-1 protein. Metabolic profiling showed that the three species produced the same metabolites, but to different extents. Liver micros omes metabolized the (-) enantiomer to 2-(N-2-thienylethylamino)-5-hyd roxytetralin, 2-(N-propylamino)-5-hydroxytetralin, and opyl-N-2-thieny lethylamino)-5,6-dihydroxytetralin, a catechol metabolite. Due to the weak dopaminergic affinities of the N-dealkylated compounds and the hi gh metabolic conversion of the catechol, no therapeutic effects of the se compounds may be expected in vivo.