Studies on the metabolic bioactivation of haloperidol (HP) and its tetrahydropyridine dehydration product

Abstract

Haloperidol (HP), a member of the butyrophenone class of neuroleptics and a first choice for the treatment of schizophrenia, causes severe extrapyramidal side effects including acute dystonic reactions, akathisia, drug-induced parkinsonism and, following chronic treatment, tardive dyskinesias (TD). The persistence of TD in some patients after neuroleptic drug treatment has been discontinued suggests that this condition may be related to a drug-induced neuronal lesion.

HP and its tetrahydropyridine dehydration product {4-(4-chlorophenyl)-1- [4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) share structural features with the parkinsonian inducing neurotoxin 1-Methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Consequently, we have elected to examine the metabolic fate of HP and HPTP to determine if these compounds, like MPTP, undergo metabolic bioactivation to neurotoxic pyridinium metabolites.

In vitro metabolic studies have demonstrated that human monoamine oxidase A and cytochrome P450 3A4 are capable of catalyzing the oxidation of HPTP and/or HP to the toxic HP pyridinium metabolite {4-(4-chlorophenyl)-1-[4- (4-fluorophenyl)-4-oxobutyl]pyridinium species (HPP⁺). Rodent liver and brain preparations also catalyze HPP⁺ formation. In vivo studies in human and rodents have led to the characterization of both HPP⁺ and RHPP⁺, that is the pyridinium metabolite derived from reduced haloperidol, a major circulating metabolite of HP. Quantitative estimates of HPP⁺/RHPP⁺ in several patients receiving high doses of HP have been recorded. RHPP⁺ is the major urinary pyridinium metabolite in humans while HPP⁺ is the major pyridinium metabolite in rodents. Both pyridinium species also were identified in the brains of mice treated with HPTP but not with HP. Toxicological studies in baboons have demonstrated HPP⁺ and RHPP⁺ formation in this animal model. This is an ongoing study that should lead to useful toxicological results.

Finally, [³H]HPTP was synthesized and in vivo (mouse) and in vitro (brain) metabolism studies were carried out in C57BL/6 mice. We attempted to gain some insight into the very low mass balance observed in our earlier work. This issue remains unresolved. The results obtained with the tritiated compound suggested that the major radioactive metabolite of HPTP in this species is the pyridinium metabolite HPP⁺. Overall these results emphasize the importance of pyridinium metabolite formation and argue for more extensive toxicological work to assess the possible contribution of HPP⁺ and RHPP⁺ to the extrapyramidal side effects caused by HP.