Dehydration is the first step in the bioactivation of haloperidol to its pyridinium metabolite

doi:10.1016/0378-4274(91)90062-B

Toxicology Letters

Volume 59, Issues 1–3, December 1991, Pages 117-123

https://doi.org/10.1016/0378-4274(91)90062-B Get rights and content

Abstract

Haloperidol was found to have a similar metabolic pathway to that of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) in mice microsomal preparations. The 1,2,3,6-tetrahydropyridine derivative of haloperidol was detected in NADPH-fortified metabolic incubation mixtures of haloperidol. Incubation of this dehydrated haloperidol produced the pyridinium metabolite. These metabolites were confirmed by comparison with synthesised compounds using HPLC and HPLC-MS. Dehydration of an alcohol to a double bond represents a novel metabolic pathway. This novel metabolic pathway indicates a MPTP-like mechanism for the Parkinsonism observed with haloperidol in clinical use.

References (9)

W. Soudijn et al.
Distribution, excretion and metabolism of neuroleptics of the butyrophenone type
Eur. J. Pharmacol.
(1967)
G.C. Davis et al.
Chronic parkinsonism secondary to intravenous injection of meperidine analogues
Psychiatry Res.
(1979)
B. Subramanyam et al.
Identification of a potentially neurotoxic pyridinium metabolite of haioperidol in rats
Biochem. Biophys. Res. Commun.
(1990)
A. Forsman et al.
The metabolism of haloperidol
Curr. Ther. Res.
(1978)

There are more references available in the full text version of this article.

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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.
Brain extraction of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a neurotoxic metabolite of haloperidol: Studies using [3H]HPP+
2002, Japanese Journal of Pharmacology
Tritium-labeled 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP⁺) was synthesized enzymatically from [³H]haloperidol using rat liver microsomal preparations, and using prepared [³H]HPP⁺, the passage of HPP+ into the brain was investigated. Consequently, HPP⁺ showed a moderate brain uptake index, indicating that it is able to permeate the blood-brain barrier. Furthermore, HPP⁺ was detected in murine brains after being intravenously injected. These results suggested that HPP⁺, produced mainly in the liver, is taken up into the brain and induces damage to brain dopaminergic neurons.
Determination of 1-methyl-1,2,3,4-tetrahydroisoquinoline in mouse brain after treatment with haloperidol by gas chromatography-selected ion monitoring
1999, Journal of Chromatography B: Biomedical Sciences and Applications
The content of the endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ), in mouse brain, treated with the antipsychotic agent haloperidol (HP) was determined by GC–SIM (selected ion monitoring) system. 1-MeTIQ in brain was extracted with chloroform at pH 11–12 and was detected as PFP derivative by GC–SIM. The 1-MeTIQ contents in mouse brains following intraperitoneal administration of HP or its dehydrated product, HPTP (1 and 4 mg/kg per day, for four days), were markedly reduced compared with control groups. This result agrees well with the findings in human idiopathic parkinsonianism and in MPTP-treated mouse brain. In addition, this finding suggests that the change of the endogenous amine 1-MeTIQ content in the brain plays an important role in the pathogenesis of toxin-induced parkinsonism.
p-Fluorophenylglycine in the urine of baboons treated with HPTP, the tetrahydropyridine analog of haloperidol
1999, Life Sciences
We report the presence of p-fluorophenylglycine (p-FPG) in the urine of six baboons treated with HPTP, the tetrahydropyridine dehydration product of haloperidol (HP). Oxidative N-dealkylation, the major metabolic pathway of HP, gives rise to 3-(4-fluorobenzoyl)propionic acid (p-FBPA). Subsequent β-oxidation of p-FBPA produces p-fluorophenylacetic acid (p-FPA). The presence of p-FPA argues for the formation also of p-fluorophenylglyoxylic acid (p-FPGA) derived from β-oxidation of p-FBPA. Plasma aminotransferases should convert p-FPGA to p-FPG. The presence of p-FPG in these animals suggest the presence of phenylglycine aminotransferases in the baboon and possibly also in other primates, including the human. Reports by other authors found that treatment with α-phenylglycine (α-PG), an “unnatural” amino acid, leads to striatal dopamine (DA) depletion in rabbits — an effect explained on the basis of α-PG competing with DA for the neuronal vesicular storage sites. We performed in vitro DA release assays in mouse striatal synaptosomal preparations but found that neither α-PG nor p-FPG released any DA. It therefore remains unclear whether p-FPG may be a contributing factor to neurologic side-effects such as tardive dyskinesia (TD) found in patients after long-term HP treatment.
Orphan neurones and amine excess: The functional neuropathology of Parkinsonism and neuropsychiatric disease
1998, Brain Research Reviews
The aetiology and treatment of Parkinsonism is currently conceptualised within a dopamine (DA) deficiency-repletion framework. Loss of striatal DA is thought to cause motor impairment of which tremor, bradykinaesia and rigidity are prominent features. Repletion of deficient DA should at least minimise parkinsonian signs and symptoms. In Section 2, based on extensive pre-clinical and clinical findings, the instability of this approach to Parkinsonism is scrutinised as the existing negative findings challenging the DA deficiency hypothesis are reviewed and reinterpreted. In Section 3it is suggested that Parkinsonism is due to a DA excess far from the striatum in the area of the posterior lateral hypothalamus (PLH) and the substantia nigra (SN). This unique area, around the diencephalon/mesencephalon border (DCMCB), is packed with many ascending and descending fibres which undergo functional transformation during degeneration, collectively labelled `orphan neurones'. These malformed cells remain functional resulting in pathological release of transmitter and perpetual neurotoxicity. Orphan neurone formation is commonly observed in the PLH of animals and in man exhibiting Parkinsonism. The mechanism by which orphan neurones impair motor function is analogous to that seen in the diseased human heart. From this perspective, to conceptualise orphan neurones at the DCMCB as `Time bombs in the brain' is neither fanciful nor unrealistic [E.M. Stricker, M.J. Zigmond, Comments on effects of nigro-striatal dopamine lesions, Appetite 5 (1984) 266–267] as the DA excess phenomenon demands a different therapeutic approach for the management of Parkinsonism. In Section 4the focus is on this novel concept of treatment strategies by concentrating on non-invasive, pharmacological and surgical modification of functional orphan neurones as they affect adjacent systems. The Orphan neurone/DA excess hypothesis permits a more comprehensive and defendable interpretation of the interrelationship between Parkinsonism and schizophrenia and other related disorders.
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.

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^☆: This paper is dedicated to Professor H. Oelschlager, Director of The Institute of Pharmaceutical Chemistry, University of Frankfurt, on the occasion of this 70th birthday.

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Toxicology Letters

Abstract

References (9)

Distribution, excretion and metabolism of neuroleptics of the butyrophenone type

Eur. J. Pharmacol.

Chronic parkinsonism secondary to intravenous injection of meperidine analogues

Psychiatry Res.

Identification of a potentially neurotoxic pyridinium metabolite of haioperidol in rats

Biochem. Biophys. Res. Commun.

The metabolism of haloperidol

Curr. Ther. Res.

Cited by (57)

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

Brain extraction of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP<sup>+</sup>), a neurotoxic metabolite of haloperidol: Studies using [<sup>3</sup>H]HPP<sup>+</sup>

Determination of 1-methyl-1,2,3,4-tetrahydroisoquinoline in mouse brain after treatment with haloperidol by gas chromatography-selected ion monitoring

p-Fluorophenylglycine in the urine of baboons treated with HPTP, the tetrahydropyridine analog of haloperidol

Orphan neurones and amine excess: The functional neuropathology of Parkinsonism and neuropsychiatric disease

Effects of haloperidol metabolites on neurotransmitter uptake and release: Possible role in neurotoxicity and tardive dyskinesia

Dehydration is the first step in the bioactivation of haloperidol to its pyridinium metabolite☆

Abstract

Eur. J. Pharmacol.

Psychiatry Res.

Biochem. Biophys. Res. Commun.

The metabolism of haloperidol

Curr. Ther. Res.