The Metabolism of Chlorpromazine N-Oxide in the Rat

Abstract

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single oral dose. 2. Metabolites identified in both urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. 3. Metabolites were separated by h.p.l.c. or g.l.c. prior to mass spectrometric analysis. The structures of the metabolites were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic compounds. 4. Chlorpromazine N-oxide and any metabolite which retained the intact N-oxide function, such as chlorpromazine, N,S-dioxide, could not be identified in any of the extracts. 5. When 3H-chlorpromazine N-oxide was administered under the same conditions; approximately twice as much radioactivity was excreted in the faeces (52.1 +/- 9.7%) as in the urine (26.9 +/- 7.2%).

Synthesis of the N-Oxides of Phenothiazine Antipsychotic Agents

“…The excess manganese dioxide was filtered, and the solvent from the filtrate was removed on a rotavapor. The residue was dissolved in dry methanol (20 , aromatic C,-H), 8.05 (dd, 1H, J = 0.8,7.6 Hz, aromatic C,-H), 7.95 (bd, lH, J = 8.6 Hz, aromatic C,-H), 7.85 (dt, 1H, J = 0.8,7.5 Hz, aromatic C,-H), 7. 81 (dd, lH, J = 1.3,8.2 Hz, aromatic Cs-H), 7 azine ( 2 b 5 b , respectively). Thus, it was demonstrated that the aliphatic tertiary amine nitrogen underwent oxidation irrespective of whether it was acyclic as in chlorpromazine, cyclic as in the pipermine type phenothiazines fluphenazine, piperidine-type phenothiazine sulforidazine.…”

“…7,8,20,21 Specifically, samples of the N-oxides of chlorpromazine (la), fluphenazine (2a), prochlorperazine (3a), sulforidazine (4a), and trifluoperazine (5a) were required; procedures for the chemical synthesis have been reported for only the first two cases.11J2J4-16 Various oxidizing agents were examined in the present work with a view to develop a general procedure for the chemical synthesis of the N-oxide metabolites of phenothiazine antipsychotic agents.…”

Investigation of the electrochemical oxidation products of zotepine and their fragmentation using on‐line electrochemistry/electrospray ionization mass spectrometry

“…As for the phase I metabolism of chlorpromazine, N-demethylation, S-oxidation, N-oxidation and aromatic hydroxylation have also been reported, 29 and are comparable to that of zotepine. In our study, the oxidized metabolite, which appears to be sulfoxide, and its N-demethylated compound were detected, confirming that some P450 metabolites were mimicked by the EC/ESI-MS system.…”

The metabolism of chlorpromazineN-oxide in man and dog

“…The present procedures for the extraction of chlorpromazine N-oxide and its metabolites from urine and faeces of dog and man are simplified versions of those published recently for such studies in rat (Jaworski et al 1988). This was possible because for dog and man, unlike the rat, polar solvent (pentane-dichloromethane-2propanol) extracts of urine and faeces when analysed by h.p.1.c.…”

“…In the first report the intraperitoneal administration of chlorpromazine N-oxide to rat resulted in significant concentrations of chlorpromazine, N-desmethylchlorpromazine and 7-hydroxychlorpromazine in brain, and of the former two compounds in serum (Alfredsson et al 1977). In a subsequent systematic metabolic study of oral chlorpromazine N-oxide in rat (Jaworski et al 1988), the identification of chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide has been demonstrated in urine and faeces. There are no reports of the in vivo metabolic conversion of chlorpromazine N-oxide in man or species other than rat.…”