title: Dehydration is the first step in the bioactivation of haloperidol to its pyridinium metabolite.
abstract: Haloperidol was found to have a similar metabolic pathway to that of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice microsomal preparations. The 1,2,3,6-tetrahydropyridine derivative of haloperidol was detected in NADPH-fortified metabolic incubation mixtures of haloperidol. Incubation of this dehydrated haloperidol produced the pyridinium metabolite. These metabolites were confirmed by comparison with synthesised compounds using HPLC and HPLC-MS. Dehydration of an alcohol to a double bond represents a novel metabolic pathway. This novel metabolic pathway indicates a MPTP-like mechanism for the Parkinsonism observed with haloperidol in clinical use.
authors.affiliation: Chelsea Department of Pharmacy, King's College, University of London, U.K.
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.forename: J W
authors.initials: JW
authors.lastname: Gorrod
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000493:pharmacokinetics*; D015655:1-Methyl-4-phenylpyridinium / Q000737:chemistry; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006220:Haloperidol / Q000009:adverse effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium