title: On the metabolism of haloperidol.
abstract: 1. p-Fluorobenzoyl-propionic acid, 4-(4-chlorophenyl)-4-hydroxy-piperidine, and reduced haloperidol were confirmed as metabolites of haloperidol. Their formation was catalysed by hepatic microsomes and was NADPH dependent. 2. The pyridinium metabolite of haloperidol (HP+) was identified. It is proposed that haloperidol first undergoes dehydration to form its 1,2,3,6-tetrahydropyridine analogue (HTP). HTP is then further metabolized to HP+, HTP N-oxide and its N-dealkylated product, 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP). HTPN-oxide was metabolized to CPTP and HTP. All these metabolites were confirmed by comparison with synthesized compounds using h.p.l.c. and h.p.l.c.-mass spectrometry. 3. Three unknown metabolites were present in microsomal metabolic incubations of haloperidol. One of them was tentatively characterized by h.p.l.c.-mass spectrometry as an oxygenated product of haloperidol, another appears to be the 2-pyridine analogue of haloperidol. The third metabolite was shown to be a neutral compound of unknown structure, which was not haloperidol N-oxide nor 4-hydroxy-4'-fluorobutyrophenone. In addition, HTP was metabolized to a further unknown product with a similar u.v. spectrum to that of HTP. 4. The identification of these metabolites led to the hypothesis that the metabolism of haloperidol is similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and may therefore produce motor neurone toxicity by a similar mechanism.
authors.affiliation: Chelsea Department of Pharmacy, King's College, University of London, UK.
authors.forename: J W
authors.initials: JW
authors.lastname: Gorrod
authors.forename: J
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D006168:Guinea Pigs; D006220:Haloperidol / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006220:Haloperidol