title: Metabolic studies on haloperidol and its tetrahydropyridinyl dehydration product (HPTP) in C57BL/6 mouse brain preparations.
abstract: The neuroleptic agent haloperidol (HP) and its tetrahydropyridinyl dehydration product HPTP are biotransformed by humans, baboons and rodents to the HP pyridinium (HPP(+)) and reduced HP pyridinium (RHPP(+)) species, potential neurotoxic metabolites that have been detected in the brain. HPP(+), however, does not pass the mouse blood-brain barrier since it is not detected in the brain following systemic administration. We report here that C57BL/6 mouse brain preparations catalyze the oxidation of HP and HPTP to HPP(+). The initial rate of HPP(+) formation from HPTP by whole brain homogenates was estimated to be approximately 20 times faster than that observed with HP as substrate. HPTP also was converted to HPP(+) by mouse brain microsomal preparations and brain slices. These results suggest that the presence of HPP(+) in the C57BL/6 mouse brain following systemic administration of HPTP may be due primarily to its in situ metabolism to HPP(+). Attempts to identify the catalyst responsible for these biotransformations, however, have not been successful.
authors.affiliation: Harvey W. Peters Center, Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA. ncastagn@vt.edu
authors.forename: Etsuko
authors.initials: E
authors.lastname: Usuki
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bloomquist
authors.forename: Ethan
authors.initials: E
authors.lastname: Freeborn
authors.forename: Kay
authors.initials: K
authors.lastname: Casagnoli
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van Der Schyf
authors.forename: Neal
authors.initials: N
authors.lastname: Castagnoli