N-GLUCURONIDATION OF ALIPHATIC TERTIARY-AMINES IN HUMAN - ANTIDEPRESSANT VERSUS ANTIPSYCHOTIC-DRUGS()

1. Metabolic N+-glucuronidation of aliphatic tertiary amine antidepres sant or antipsychotic drugs was investigated in man. In each case, uri ne was collected either from patients and/or from healthy volunteers w ho were administered the drug orally. 2. Metabolites were separated by hplc and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite id entified as a quaternary ammonium-linked glucuronide metabolite was co nfirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of an authentic standard synthesized in these labo ratories. 3. Of the 10 antipsychotic drugs examined clozapine and loxa pine were the only two for which the N+-glucuronidation pathway was ob served, whereas all four antidepressants gave the respective NC-glucur onide metabolite. 4. The N+-glucuronide metabolites in 24h urine sampl es were quantified by hplc. The mean (n = 3) percentage of the dose ex creted as the metabolite was found to be 1.6 and 3.1% in the cases of the antipsychotic agents loxapine and clozapine respectively, whereas for the antidepressants clomipramine, imipramine, trazodone and trimip ramine these means varied between 0.1 and 0.8%.