Studies on the metabolism of haloperidol (HP): The role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP + found in rat brain following ip administration of HP

Abstract

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 + levels in brain tissues increased gradually during the same period. HPP + levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP + also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP + was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP + with 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 nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP + from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.