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.
