title: Metabolic studies on haloperidol and its tetrahydropyridine analog in C57BL/6 mice.
abstract: The neuroleptic agent haloperidol (HP) is biotransformed in humans to a pyridinium metabolite, HPP+, that displays neurotoxic properties resembling those of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-derived neurotoxic pyridinium metabolite MPP+. We report here that HP and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP) are metabolized in vivo by the MPTP-susceptible C57BL/6 mouse to several pyridinium metabolites including HPP+ and the 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-hydroxybutyl]pyridinium species RHPP+, the pyridinium species corresponding to reduced haloperidol (RHP), a major circulating metabolite of HP. Atmospheric pressure ion-spray (API) mass spectral data also suggest the formation of fluorophenyl ring-hydroxylated derivatives of these two pyridinium metabolites. Furthermore, HPLC tracings reveal the presence of HPP+, RHPP+, and two phenolic pyridinium metabolites in brain tissue extracts of HPTP, but not HP, treated mice. The neurotoxic potential of MPTP-type pyridinium species suggests that these metabolites may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.
authors.affiliation: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061-0212.
authors.forename: C J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: K
authors.initials: K
authors.lastname: Castagnoli
authors.forename: E
authors.initials: E
authors.lastname: Usuki
authors.forename: H G
authors.initials: HG
authors.lastname: Fouda
authors.forename: J M
authors.initials: JM
authors.lastname: Rimoldi
authors.forename: N
authors.initials: N
authors.lastname: Castagnoli
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006220:Haloperidol / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000378:metabolism; D013050:Spectrometry, Fluorescence
chemical_list: D009498:Neurotoxins; C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006220:Haloperidol