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%.

Biotransformation of benzydamine by microsomes and precision-cut slices prepared from cattle liver

“…Examples include imipramine, clomipramine, clozapine, chlorpromazine, trazodone, loxapine and trimipramine (Luo et al 1995, Dain et al 1997, but there are no reports in the literature describing N ‡ -glucuronidated products from hydroxylated BZ or reports on the ability of cattle to perform N ‡ -glucuronidation. Until now, only the rabbit, unlike the other laboratory species (dog, rat, cat) is reported to share this metabolic pathway with humans.…”

Role of Human UGT2B10 inN-Glucuronidation of Tricyclic Antidepressants, Amitriptyline, Imipramine, Clomipramine, and Trimipramine

“…The quaternary N-glucuronides of TCAs were major phase II metabolites identified in human urine (Luo et al, 1995). The steady-state plasma concentrations of amitriptyline, imipramine, clomipramine, and trimipramine are approximately 0.2, 0.6, 0.2, and 0.2 M, respectively (Bailey and Jatlow, 1976;Musa, 1989;Reis et al, 2009).…”

“…The quaternary ammonium glucuronides of a number of TCAs, including amitriptyline, imipramine, clomipramine, and trimipramine ( Fig. 1), have been identified as major phase II metabolites in human urine (Luo et al, 1995). The urinary excretion of amitriptyline Nglucuronide metabolite was 2.5 to 21% of the oral dose administered (Breyer-Pfaff et al, 1997).…”

ImipramineN-Glucuronidation in Human Liver Microsomes: Biphasic Kinetics and Characterization of UDP-Glucuronosyltransferase Isoforms

“…The percentage of the dose excreted in urine as imipramine N-glucuronide was reported to be 0.2% (Luo et al, 1995). Until now, imipramine N-glucuronide formed by in vitro assay This study was supported by a grant for research on health sciences focusing on drug innovation from the Japan Health Sciences Foundation.…”