Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.
1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.
Beckett
A H
AH
Chelsea Department of Pharmacy, King's College London, University of London, UK.
Navas
G E
GE
Hutt
A J
AJ
D000818:Animals; D001711:Biotransformation; D002746:Chlorpromazine / Q000378:metabolism*; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D003903:Deuterium; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011395:Promazine / Q000378:metabolism*; D011817:Rabbits
D003903:Deuterium; D011395:Promazine; D002746:Chlorpromazine