METABOLIC STUDIES ON HALOPERIDOL AND ITS TETRAHYDROPYRIDINE ANALOG INC57BL 6 MICE/

The neuroleptic agent haloperidol (HP) is biotransformed in humans to a pyridinium metabolite, HPP+, that displays neurotoxic properties res embling those of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPT P)-derived neurotoxic pyridinium metabolite MPP(+). We report here tha t HP and its tetrahydropyridine dehydration product uorophenyl)-4-oxob utyl]-1,2,3,6-tetrahydropyridine (HPTP) are metabolized in vivo by the MPTP-susceptible C57BL/6 mouse to several pyridinium metabolites incl uding HPP+ and the l)-1-[4-(4-fluorophenyl)-4-hydroxybutyl]pyridinium species RHPP(+), the pyridinium species corresponding to reduced halop eridol (RHP), a major circulating metabolite of HP. Atmospheric pressu re ionspray (API) mass spectral data also suggest the formation of flu orophenyl ring-hydroxylated derivatives of these two pyridinium metabo lites. 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 s ome of the neurological disorders observed in humans undergoing chroni c HP treatment.