STUDIES ON THE METABOLISM OF HALOPERIDOL (HP) - THE ROLE OF CYP3A IN THE PRODUCTION OF THE NEUROTOXIC PYRIDINIUM METABOLITE HPP-BRAIN FOLLOWING IP ADMINISTRATION OF HP( FOUND IN RAT)

The levels of haloperidol [HP] and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated ip with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ le vels in brain tissues increased gradually during the same period. HPP levels in brain tissues increased further when HP (10 mg/kg) was inje cted for three consecutive days. The formation of HPP+ also was studie d in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found i n brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ wit h about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and ni fedipine and by an anti-CYP3A antibody. These results suggest that for mation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed m ainly by CYP3A although the participation of other P450 forms cannot b e ruled out.