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.