Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem

We have shown in patients taking the antipsychotic drug haloperidol (HP) that two pyridinium metabolites (HPP+ and RHPP(+)) are present in blood and urine in nM concentrations. These metabolites are structurally analogous to MPP(+), the neurotoxic metabolite of the well-known parkinsonian-producing protoxin, MPTP. In this study we measured the concentrations of HPP+ and RHPP(+) in seven regions of the brain (putamen, substantia nigra, globus pallidus, caudate, hippocampus, cerebellum and occipital cortex) obtained at post-mortem from three patients who were taking HP before death. Blood, urine, and bile from one patient were analysed as well. HPP+ was present in all regions (except for substantia nigra in one patient and globus pallidus in another); the amount/g ranged from 1.6 - 8.3 pMol but there was no preferential sequestration of the metabolite in dopaminergic regions. Similarly RHPP(+) was present relatively uniformly in all regions; the amount/g ranged from 1.1 - 7.6 pMol. The concentrations of HPP+ and RHPP(+) in one patient were 24 and 13 nM in blood, 660 and 230 nM in urine, and 13.0 and 1.4 mu M in bile, respectively. The presence of these pyridinums in brain adds another important piece of information to the case that, at least for HP, metabolite-induced neurotoxicity could contribute to the extrapyramidal side-effects in patients receiving long-term therapy.