2 PYRIDINIUM METABOLITES OF HALOPERIDOL ARE PRESENT IN THE BRAIN OF PATIENTS AT POSTMORTEM

We have shown in patients taking the antipsychotic drug haloperidol (H P) that two pyridinium metabolites (HPP+ and RHPP(+)) are present in b lood and urine in nM concentrations. These metabolites are structurall y analogous to MPP(+), the neurotoxic metabolite of the well-known par kinsonian-producing protoxin, MPTP. In this study we measured the conc entrations of HPP+ and RHPP(+) in seven regions of the brain (putamen, substantia nigra, globus pallidus, caudate, hippocampus, cerebellum a nd occipital cortex) obtained at post-mortem from three patients who w ere taking HP before death. Blood, urine, and bile from one patient we re analysed as well. HPP+ was present in all regions (except for subst antia nigra in one patient and globus pallidus in another); the amount /g ranged from 1.6 - 8.3 pMol but there was no preferential sequestrat ion of the metabolite in dopaminergic regions. Similarly RHPP(+) was p resent relatively uniformly in all regions; the amount/g ranged from 1 .1 - 7.6 pMol. The concentrations of HPP+ and RHPP(+) in one patient w ere 24 and 13 nM in blood, 660 and 230 nM in urine, and 13.0 and 1.4 m u M in bile, respectively. The presence of these pyridinums in brain a dds another important piece of information to the case that, at least for HP, metabolite-induced neurotoxicity could contribute to the extra pyramidal side-effects in patients receiving long-term therapy.