Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol

doi:10.1016/0006-291X(91)91228-5

Biochemical and Biophysical Research Communications

Volume 181, Issue 2, 16 December 1991, Pages 573-578

https://doi.org/10.1016/0006-291X(91)91228-5 Get rights and content

Abstract

Evidence that the parkinsonian inducing agent MPTP is biotransformed to a pyridinium species that selectively destroys nigrostriatal neurons in humans and subhuman primates has prompted studies to evaluate the metabolic fate of the structurally related neuroleptic agent haloperidol. With the aid of a highly sophisticated atmospheric pressure ionspray HPLC/MS/MS assay, unambiguous evidence has been obtained for the presence of the haloperidol pyridinium species in extracts of urine obtained from haloperidol-treated patients and in extracts of NADPH-supplemented human liver microsomal incubation mixtures containing haloperidol. The potential significance of the formation of this putative neurotoxic pyridinium species is considered.

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Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms
2017, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
The relationship between genotype and acute parkinsonism is less clear. Some CYP2D-mediated antipsychotic metabolites are potentially neurotoxic (Subramanyam et al., 1991; Subramanyam et al., 1990), but the relative roles of the parent and metabolites in side-effects are unknown. While brain DRD2 occupancy and resulting antipsychotic efficacy are closely related, they are not necessarily related to antipsychotic plasma levels (Tauscher et al., 2002), and this disconnect, taken with other risk factors for tardive dyskinesia, such as gender, age and length of illness, make it difficult to identify sources of inter-individual variation in risk for side-effects.
Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model.
Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects.
Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations.
Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects.
Brain levels of the neurotoxic pyridinium metabolite HPP+ and extrapyramidal symptoms in haloperidol-treated mice
2013, NeuroToxicology
Citation Excerpt :
Therefore, it is plausible that HPP+ contributes to the pathophysiological effects of haloperidol via toxicity similar to that of MPP+. Consistent with this notion, HPP+ is found in post-mortem brain tissue, plasma and urine from patients with schizophrenia chronically treated with haloperidol (Eyles et al., 1994, 1997; Avent et al., 1997; Subramanyam et al., 1991). A positive relationship between the severity of TD and peripheral blood levels of HPP+ has been reported by two studies of a total of 51 haloperidol-treated patients (Iwahashi et al., 2001; Ulrich et al., 2005).
The typical antipsychotic haloperidol is a highly effective treatment for schizophrenia but its use is limited by a number of serious, and often irreversible, motor side effects. These adverse drug reactions, termed extrapyramidal syndromes (EPS), result from an unknown pathophysiological mechanism. One theory relates to the observation that the haloperidol metabolite HPP+ (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium) is structurally similar to MPP+ (1-methyl-4-phenylpyridinium), a neurotoxin responsible for an irreversible neurodegenerative condition similar to Parkinson's disease. To determine whether HPP+ contributes to haloperidol-induced EPS, we measured brain HPP+ and haloperidol levels in strains of mice at high (C57BL/6J and NZO/HILtJ) and low (BALB/cByJ and PWK/PhJ) liability to haloperidol-induced EPS following chronic treatment (7–10 adult male mice per strain). Brain levels of HPP+ and the ratio of HPP+ to haloperidol were not significantly different between the haloperidol-sensitive and haloperidol-resistant strain groups (P = 0.50). Within each group, however, strain differences were seen (P < 0.01), indicating that genetic variation regulating steady-state HPP+ levels exists. Since the HPP+ levels that we observed in mouse brain overlap the range of those detected in post-mortem human brains following chronic haloperidol treatment, the findings from this study are physiologically relevant to humans. The results suggest that strain differences in steady-state HPP+ levels do not explain sensitivity to haloperidol-induced EPS in the mice we studied.
Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one
2008, Bioorganic and Medicinal Chemistry
The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED₅₀ value.
Mitochondriotropics: A review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria
2007, Journal of Controlled Release
Since compounds targeting mitochondria exhibit diverse accumulation mechanisms and chemical features, various questions arise. Do such “mitochondriotropics” have a characteristic chemistry? What are mitochondrial uptake mechanisms? Do mitochondriotropics necessarily accumulate in mitochondria or merely have access? Is the concept “mitochondriotropic” of any practical value? To seek answers, a non-biased sample of > 100 mitochondriotropics was generated from the review literature. This dataset was examined using: physicochemical classification; quantitative structure-activity relations (QSAR) models; and a Fick–Nernst–Planck physicochemical model. The ability of the latter two approaches to predict mitochondriotropic behaviour was assessed, and comparisons made between methods, and with current assumptions. All approaches provided instructive pictures of the nature of mitochondriotropics. Thus although lipophilic cations are regarded as the commonest structural type, only a third were such. Much the same proportion were acids, potentially or actually anions. Many mitochondriotropics were electrically neutral compounds. All categorizations involved overall molecular properties, not the presence of “mitochondriotropic tags” — again contrary to literature concepts. Selective mitochondrial accumulation involved electric potential, ion-trapping, and complex formation with cardiolipin; non-specific accumulation involved membrane partitioning. Non-specific access required only low lipophilicity. Mitochondrial targeting did not preclude additional accumulation sites, e.g. lysosomes. The concept “mitochondriotropic” remains useful, although may imply access, not accumulation. QSAR and Fick–Nernst–Planck approaches are complementary — neither is universally applicable. Using both approaches enabled the mitochondriotropic behavior of > 80% of the dataset to be predicted, and the physicochemistry of mitochondriotropics to be specified in some detail. This can facilitate guided syntheses and selection of optimal mitochondriotropic structures.
Effects of haloperidol and its pyridinium metabolite on plasma membrane permeability and fluidity in the rat brain
2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry
The use of antipsychotic drugs is limited by their tendency to produce extrapyramidal movement disorders such as tardive dyskinesia and parkinsonism. In previous reports it was speculated that extrapyramidal side effects associated with the butyrophenone neuroleptic agent haloperidol (HP) could be caused in part by the neurotoxic effect of its pyridinium metabolite (HPP⁺). Although both HPP⁺ and HP have been shown to induce neurotoxic effects such as loss of cell membrane integrity, no information exists about the difference in the neurotoxic potency, especially in the potency to induce plasma membrane damage, between these two agents. In the present study, we compared the potency of the interaction of HPP⁺ and HP with the plasma membrane integrity in the rat brain. Membrane permeabilization (assessed as [¹⁸F]2-fluoro-2-deoxy-d-glucose-6-phosphate release from brain slices) and fluidization (assessed as the reduction in the plasma membrane anisotropy of 1,6-diphenyl 1,3,5-hexatriene) were induced by HPP⁺ loading (at ≥ 100 μM and ≥ 10 μM, respectively), while comparable changes were induced only at a higher concentration of HP (= 1 mM). These results suggest that HPP⁺ has a higher potency to induce plasma membrane damage than HP, and these actions of HPP⁺ may partly underlie the pathogenesis of HP-induced extrapyramidal side effects.
Evaluation of the eutomer of 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan- 1-one, {(+)-SYA 09}, a pyrrolidine analog of haloperidol
2006, Bioorganic and Medicinal Chemistry Letters
Enantiomeric separation of the racemic 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan-1-one, a pyrrolidine analog of haloperidol, {(±)-SYA 09}, and subsequent binding studies revealed that most of the binding affinity at dopamine and serotonin receptors resides in the (+)-isomer {(+)-SYA 09} or the eutomer. Further pharmacological evaluation of the eutomer revealed that it has a higher affinity for the dopamine D4 (DAD4) receptor subtype (K_i = 3.6 nM) than for the DAD2 subtype (K_i = 51.1 nM) with a ratio of 14.2 (D2K_i/D4K_i ratio = 14.2). In an animal model of antipsychotic efficacy, the (+)-SYA 09 was efficacious with an ED₅₀ value of 1.6 mg/kg, ip, and at twice this value, (+)-SYA 09 did not induce significant catalepsy in rats.

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Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol

Abstract

Brain Res

Brain Res

Biochem. Biophys. Res. Comm

Biochem. Biophys. Res. Commun

Life Sci

Med. J. Aust

Acta. Psychiatr. Scand

Curr. Opin. Psychiat

J. Neural. Transm

J. Pharmacol. Exp. Ther