Chemistry:HPP+
 | |
| 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 | |
| |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C21H18ClFNO+ |
| Molar mass | 354.83 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.[1][2][3]
Formation and metabolism
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
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)
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
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
Besides HPP+, another reactive metabolite of haloperidol, RHPP+, has been detected in humans.[1][2] The parent form of RHPP+ is RHPTP.[8]
HPP+ in clinical studies of haloperidol
No relationships were found for serum concentrations of HPP+ or the ratio of serum concentrations of HPP+ and haloperidol with clinical variables (changes of Brief Psychiatric Rating Scale, Extrapyramidal Symptom Rating Scale) during the treatment of acute exacerbations of schizophrenic patients for 6 weeks.[9] In a cross section study of chronic schizophrenic patients treated with haloperidol, the patients with more severe tardive dyskinesia had an increased relative body burden of HPP+ as calculated by the ratio of HPP+ and haloperidol serum concentrations multiplied by the cumulative dose of haloperidol.[10]
References
- ↑ 1.0 1.1 1.2 1.3 "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. 2022. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Igarashi, Kazuo (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.
- ↑ "[The neurotoxicity of pyridinium metabolites of haloperidol]" (in Polish). Postepy Higieny I Medycyny Doswiadczalnej 69: 1169–1175. October 2015. doi:10.5604/17322693.1175009. PMID 26561842.
- ↑ "Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins". Polish Journal of Pharmacology 51 (1): 31–38. 1999. PMID 10389142.
- ↑ "Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats". Biochemical and Biophysical Research Communications 166 (1): 238–244. January 1990. doi:10.1016/0006-291x(90)91936-m. PMID 2302206.
- ↑ "Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite". Chemical Research in Toxicology 4 (1): 123–128. 1991. doi:10.1021/tx00019a017. PMID 1912294.
- ↑ "Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol". Biochemical and Biophysical Research Communications 181 (2): 573–578. December 1991. doi:10.1016/0006-291x(91)91228-5. PMID 1755839.
- ↑ "Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites". Chem Res Toxicol 19 (7): 914–920. July 2006. doi:10.1021/tx0600090. PMID 16841959.
- ↑ "Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment". J Clin Psychopharmacology 20 (2): 210–219. April 2000. doi:10.1097/00004714-200004000-00014. PMID 10770460.
- ↑ "Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients". Pharmacopsychiatry 38 (4): 171–177. July 2005. doi:10.1055/s-2005-871240. PMID 16025420.
 |  |
