Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: Is HPTP an intermediate?

doi:10.1016/S0024-3205(97)00955-7

Life Sciences

Volume 61, Issue 24, 7 November 1997, Pages 2383-2390

https://doi.org/10.1016/S0024-3205(97)00955-7 Get rights and content

Abstract

The metabolism of haloperidol (HP) to the potentially neurotoxic pyridinium species, HPP⁺ and RHPP⁺, has been demonstrated in humans. In vitro studies in microsomes harvested from various animal species indicate that the tetrahydropyridines, HPTP and RHPTP, could be intermediates in this pathway. However, this has not yet been demonstrated in vivo in humans. In this study, plasma and urine collected from eight critically ill patients treated with high doses of intravenous HP were analyzed for HPTP and RHPTP using HPLC with electrochemical detection. However, neither HPTP nor RHPTP were detected despite plasma concentrations of HP and RHP higher than any previously reported. HPP⁺ and RHPP⁺ were both present in the urine in high concentrations and accounted for 1.1 ± 0.5% and 5.3 ± 3.6%, respectively, of the administered dose of HP. The apparent elimination half-lives of HPP⁺ and RHPP⁺ were 67.3 ± 11.0 hr and 63.3 ± 11.6 hr, respectively. The absence of HPTP and RHPTP in plasma and urine suggests that in humans these tetrahydropyridines either are insignificant intermediates in the metabolism of HP in vivo or are present only transiently at their site of formation and are not released into the circulation.

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Cited by (24)

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.
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.
Liquid chromatographic-mass spectrometric determination of haloperidol and its metabolites in human plasma and urine
2002, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Haloperidol and its two metabolites, reduced haloperidol and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP) in human plasma and urine were analyzed by HPLC–MS using a new polymer column (MSpak GF-310), which enabled direct injection of crude biological samples without pretreatment. Recoveries of haloperidol and reduced haloperidol spiked into plasma were 64.4–76.1% and 46.8–50.2%, respectively; those for urine were 87.3–99.4% and 94.2–98.5%, respectively; those of CPHP for both samples were not less than 92.7%. The regression equations for haloperidol, reduced haloperidol and CPHP showed good linearity in the ranges of 10–800, 15–800 and 400–800 ng/ml, respectively, for both plasma and urine. Their detection limits were 5, 10 and 300 ng/ml, respectively, for both samples. Thus, the present method was sensitive enough for detection and determination of high therapeutic and toxic levels for haloperidol and its metabolites present in biological samples.
Clinical and neuropathological abnormalities in baboons treated with HPTP, the tetrahydropyridine analog of haloperidol
1999, Experimental Neurology
Tardive dyskinesia (TD) is relatively common among psychiatric patients on maintenance therapy with typical neuroleptics and persists in more than 20% even after withdrawal of the medication. Such persistence suggests an underlying pathology due to neurotoxicity. We present evidence for such a neurotoxic mechanism in a baboon model of TD. Four baboons were treated chronically with the dehydration product of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP), which is metabolized, similarly to haloperidol, to two neurotoxic pyridinium species. The animals developed orofacial dyskinesia which persisted after HPTP was ceased. Serial sections of the entire brain from the four treated animals and four vehicle-treated controls revealed volume loss in the basal forebrain and hypothalamus. Histological evaluation demonstrated a reduction in the density of magnocellular neurons in the anterior region of the nucleus basalis of Meynert (NbM). We speculate that the loss of these NbM neurons may be associated with the persistent orofacial dyskinesia observed in the HPTP-treated animals. These findings may contribute to a better understanding of neuroleptic-induced TD.
Effects of haloperidol metabolites on neurotransmitter uptake and release: Possible role in neurotoxicity and tardive dyskinesia
1998, Brain Research
This research explored the effects of haloperidol (HP) metabolites on biogenic amine uptake and release, and compared them to those of MPTP and its toxic metabolite, MPP⁺. In synaptosome preparations from mouse striatum and cortex, the HP metabolites haloperidol pyridinium (HPP⁺), reduced haloperidol pyridinium (RHPP⁺), and haloperidol tetrahydropyridine (HPTP) inhibited the presynaptic uptake of dopamine and serotonin, with greater affinity for the serotonin transporter. HPP⁺ was the most potent inhibitor of dopamine uptake, and HPTP of serotonin uptake, both with IC₅₀ values in the low micromolar range. RHPP⁺ was less active than the other metabolites, but was more active than the parent compound, HP. Inhibition of uptake was reversed when free drug was removed by centrifugation and then resuspension of the synaptosomes in fresh buffer, suggesting that inhibition of uptake was due to interaction with the transporters and was not due to irreversible cytotoxicity. HPP⁺ showed noncompetitive inhibition of both serotonin and dopamine uptake, suggesting that it has a relatively slow dissociation rate for its interaction with the transporter proteins. In experiments on amine release, HPP⁺ and HPTP were four-fold less potent than MPP⁺ for releasing preloaded dopamine from striatal synaptosomes, and only MPP⁺-dependent release was antagonized by the uptake blocker, mazindol. In contrast, RHPP⁺ displayed little ability to release either amine neurotransmitter. HPTP was about two-fold more potent than MPP⁺ for releasing serotonin from cortical synaptosomes, whereas HPP⁺ was less active than MPP⁺. The specific serotonin transport blocker fluoxetine was only able to antagonize release induced by MPP⁺. These results suggest that HP metabolites bind to the transporters for dopamine and serotonin, but are not transporter substrates. In contrast to their potent effects on amine release, HPP⁺ and HPTP were unable to release preloaded GABA from cortical synaptosomes. The implications of these results concerning a possible role of HP metabolites in the development of tardive dyskinesia are discussed.
Classics in Chemical Neuroscience: Haloperidol
2017, ACS Chemical Neuroscience

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Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: Is HPTP an intermediate?

Abstract

Biochem Biophys Res Comm

Biochem Biophys Res Comm

Life Sci

Biochem Pharmacol

Toxicol Lett

J Chromatog

J Chromatog

Life Sci

Chem Res Toxicol