The Possible Role of an Active Metafbollte Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism

Abstract

This report summarizes the case for development of extrapyramidal sideeffects associated with chronic haloperidol (HP) use, such as drug-induced parkinsonism and tardive dyskinesia. The involvement of neurotoxic metabolites has been proposed as an idea. The results from metabolic studies have demonstrated that HP is oxidatively converted to the pyridinium metabolite, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl] pyridinium species (HPP⁺), which structurally resembles the dopaminergic neurotoxin, 1-methyl-4phenylpyridinium species (MPP). The conversion is mediated by the CYP3A isoform of cytochrome P450 in the liver microsomes of animals and humans. HPP⁺ levels in rat brain increased gradually after intraperitoeal administration of HP. Moreover, in vivo microdialysis techniques revealed HPP⁺ in rat brain following administration of HP. It may have been formed peripherally and then transported through the blood-brain barrier. The results from intracerebral microdialysis and neuronal cell culture studies have shown that the pyridinium metabolite HPP⁺ derived from HP has toxic effects on dopaminergic and serotonergic neurons resembling those of the neurotoxin MPP+. Therefore, it is possible that the active metabolite of haloperidol, HPP⁺, may be involved in the development of extrapyramida sideeffects with chronic HP therapy.