N⁺ -Glucuronidation of aliphatic tertiary amines in human: antidepressant versus antipsychotic drugs

Abstract

1. Metabolic N⁺-glucuronidation of aliphatic tertiary amine antidepressant or antipsychotic drugs was investigated in man. In each case, urine was collected either from patients and/or from healthy volunteers who 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 identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of an authentic standard synthesized in these laboratories.

3. Of the 10 antipsychotic drugs examined clozapine and loxapine were the only two for which the N⁺-glucuronidation pathway was observed, whereas all four antidepressants gave the respective N⁺-glucuronide metabolite.

4. The N⁺-glucuronide metabolites in 24 h urine samples were quantified by hplc. The mean (n = 3) percentage of the dose excreted 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 trimipramine these means varied between 0.1 and 0.8%.