HPP+
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| Other names | Haloperidol pyridinium; Haloperidol pyridinium ion; Haloperidol pyridinium cation; BCPP+; 4-CFOBP; 4-(4-Chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridinium |
| Drug class | Monoaminergic neurotoxin |
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| Formula | C21H18ClFNO+ |
| Molar mass | 354.83 g·mol−1 |
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HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.[1][2][3]
Formation and metabolism
[edit]HPP+ is formed from haloperidol, and its dehydration product HPTP, by CYP3A enzymes in the liver.[1][2][4] The compound can cross the blood–brain barrier and has been detected in the brain following haloperidol administration in both animals and humans.[2]
Neurotoxicity
[edit]HPP+ is structurally related to the selective dopaminergic neurotoxin MPTP (and its active metabolite MPP+), which induces Parkinson's disease-like symptoms in humans.[1][2] HPP+ is a neurotoxin specifically affecting serotonergic and dopaminergic neurons, and its neurotoxicity resembles that of MPTP.[2]
Extrapyramidal symptoms (EPS)
[edit]HPP+ may contribute to the development of extrapyramidal symptoms (EPS) in patients undergoing long-term haloperidol therapy.[2] An alternative theory posits that these symptoms result from long-term dopamine receptor supersensitivity, rather than direct neurotoxicity.[2]
Discovery
[edit]HPP+ was first identified as a neurotoxic metabolite of haloperidol in 1990 and 1991, many years after haloperidol was introduced clinically and following the discovery of MPTP.[2][5][6][7]
Additional metabolites
[edit]Besides HPP+, another reactive metabolite of haloperidol, RHPP+, has been detected in humans.[1][2] The parent form of RHPP+ is RHPTP.[8]
References
[edit]- ^ a b c d Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.
- ^ a b c d e f g h i Igarashi K (1998). "The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism". Journal of Toxicology: Toxin Reviews. 17 (1): 27–38. doi:10.3109/15569549809006488. ISSN 0731-3837.
- ^ Górska A, Marszałł M, Sloderbach A (October 2015). "[The neurotoxicity of pyridinium metabolites of haloperidol]" [The neurotoxicity of pyridinium metabolites of haloperidol]. Postepy Higieny I Medycyny Doswiadczalnej (in Polish). 69: 1169–1175. doi:10.5604/17322693.1175009 (inactive 1 November 2024). PMID 26561842.
{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link) - ^ Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, et al. (1999). "Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins". Polish Journal of Pharmacology. 51 (1): 31–38. PMID 10389142.
- ^ Subramanyam B, Rollema H, Woolf T, Castagnoli N (January 1990). "Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats". Biochemical and Biophysical Research Communications. 166 (1): 238–244. doi:10.1016/0006-291x(90)91936-m. PMID 2302206.
- ^ Subramanyam B, Woolf T, Castagnoli N (1991). "Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite". Chemical Research in Toxicology. 4 (1): 123–128. doi:10.1021/tx00019a017. PMID 1912294.
- ^ Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N (December 1991). "Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol". Biochemical and Biophysical Research Communications. 181 (2): 573–578. doi:10.1016/0006-291x(91)91228-5. PMID 1755839.
- ^ Avent KM, DeVoss JJ, Gillam EM (July 2006). "Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites". Chem Res Toxicol. 19 (7): 914–920. doi:10.1021/tx0600090. PMID 16841959.