Life Sci. 1995 Nov 17;57(26):2439-46.  

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.

Igarashi K, Kasuya F, Fukui M, Usuki E, Castagnoli N Jr.

Faculty of Pharmaceutical Sciences, Kobegakuin University, Kobe, Japan.

The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated
in plasma and brain tissues of rats treated i.p. 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.

PMID: 8847965 [PubMed - indexed for MEDLINE]