Pharmaceutical compound
 | |
| Clinical data | |
|---|---|
| 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 |
| ATC code |
|
| Identifiers | |
IUPAC name
| |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C21H18ClFNO |
| Molar mass | 354.83 g·mol |
| 3D model (JSmol) | |
SMILES
| |
InChI
| |
HPP, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.
Formation and metabolism
HPP is formed from haloperidol, and its dehydration product HPTP, by CYP3A enzymes in the liver. The compound can cross the blood–brain barrier and has been detected in the brain following haloperidol administration in both animals and humans.
Neurotoxicity
HPP is structurally related to the selective dopaminergic neurotoxin MPTP (and its active metabolite MPP), which induces Parkinson's disease-like symptoms in humans. HPP is a neurotoxin specifically affecting serotonergic and dopaminergic neurons, and its neurotoxicity resembles that of MPTP.
Extrapyramidal symptoms (EPS)
HPP may contribute to the development of extrapyramidal symptoms (EPS) in patients undergoing long-term haloperidol therapy. An alternative theory posits that these symptoms result from long-term dopamine receptor supersensitivity, rather than direct neurotoxicity.
Discovery
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.
Additional metabolites
Besides HPP, another reactive metabolite of haloperidol, RHPP, has been detected in humans. The parent form of RHPP is RHPTP.
References
- ^ 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.
- ^ 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]. 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.