HPP+
{{Short description|Monoaminergic neurotoxin related to MPTP and metabolites of haloperidol}}
{{DISPLAYTITLE:HPP+}}
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{{Infobox drug
| drug_name = HPP+
| image = Haloperidol pyridinium.svg
| width = 250px
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| class = Monoaminergic neurotoxin
| ATC_prefix = None
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| CAS_number = 125785-69-5
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| PubChem = 9975463
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| DrugBank = DBMET01212
| ChemSpiderID = 8151055
| UNII = 47Z7A2W953
| KEGG =
| ChEBI = 178132
| ChEMBL = 1269
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| synonyms = Haloperidol pyridinium; Haloperidol pyridinium ion; Haloperidol pyridinium cation; BCPP+; 4-CFOBP; 4-(4-Chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridinium
| IUPAC_name = 4-[4-(4-chlorophenyl)pyridin-1-ium-1-yl]-1-(4-fluorophenyl)butan-1-one
| C=21 | H=18 | Cl=1 | F=1 | N=1 | O=1 | charge = +
| SMILES = C1=CC(=CC=C1C2=CC=[N+](C=C2)CCCC(=O)C3=CC=C(C=C3)F)Cl
| StdInChI = 1S/C21H18ClFNO/c22-19-7-3-16(4-8-19)17-11-14-24(15-12-17)13-1-2-21(25)18-5-9-20(23)10-6-18/h3-12,14-15H,1-2,13H2/q+1
| StdInChIKey = KAPIKUHBALFONG-UHFFFAOYSA-N
}}
HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.{{cite book | vauthors = Kostrzewa RM | title=Handbook of Neurotoxicity | chapter=Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons | publisher=Springer International Publishing | publication-place=Cham | date=2022 | isbn=978-3-031-15079-1 | doi=10.1007/978-3-031-15080-7_53 | pages=159–198}}{{cite journal | last=Igarashi | first=Kazuo | title=The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism | journal=Journal of Toxicology: Toxin Reviews | volume=17 | issue=1 | date=1998 | issn=0731-3837 | doi=10.3109/15569549809006488 | pages=27–38}}{{cite journal | vauthors = Górska A, Marszałł M, Sloderbach A | title = [The neurotoxicity of pyridinium metabolites of haloperidol] | language = Polish | journal = Postepy Higieny I Medycyny Doswiadczalnej | volume = 69 | issue = | pages = 1169–1175 | date = October 2015 | pmid = 26561842 | doi = 10.5604/17322693.1175009 | doi-broken-date = 1 November 2024 | trans-title = The neurotoxicity of pyridinium metabolites of haloperidol | doi-access = free }}
Formation and metabolism
HPP+ is formed from haloperidol, and its dehydration product HPTP, by CYP3A enzymes in the liver.{{cite journal | vauthors = Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, Riker RR | title = Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins | journal = Polish Journal of Pharmacology | volume = 51 | issue = 1 | pages = 31–38 | date = 1999 | pmid = 10389142 | doi = }} 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.{{cite journal | vauthors = Subramanyam B, Rollema H, Woolf T, Castagnoli N | title = Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats | journal = Biochemical and Biophysical Research Communications | volume = 166 | issue = 1 | pages = 238–244 | date = January 1990 | pmid = 2302206 | doi = 10.1016/0006-291x(90)91936-m }}{{cite journal | vauthors = Subramanyam B, Woolf T, Castagnoli N | title = Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite | journal = Chemical Research in Toxicology | volume = 4 | issue = 1 | pages = 123–128 | date = 1991 | pmid = 1912294 | doi = 10.1021/tx00019a017 }}{{cite journal | vauthors = Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N | title = Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol | journal = Biochemical and Biophysical Research Communications | volume = 181 | issue = 2 | pages = 573–578 | date = December 1991 | pmid = 1755839 | doi = 10.1016/0006-291x(91)91228-5 }}
Additional metabolites
Besides HPP+, another reactive metabolite of haloperidol, RHPP+, has been detected in humans. The parent form of RHPP+ is RHPTP.{{cite journal | vauthors = Avent KM, DeVoss JJ, Gillam EM | title = Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites | journal = Chem Res Toxicol | volume = 19 | issue = 7 | pages = 914–920 | date = July 2006 | pmid = 16841959 | doi = 10.1021/tx0600090 | url = }}
HPP<sup>+</sup> 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.{{cite journal | vauthors = Ulrich S, Neuhof S, Braun V, Danos P, Pester U, Hoy L | title = Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment | journal = J Clin Psychopharmacology | volume = 20 | issue = 2 | pages = 210–219 | date = April 2000 | pmid = 10770460 | doi = 10.1097/00004714-200004000-00014 | url = }} 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.{{cite journal | vauthors = Ulrich S, Sandmann U, Genz A | title = Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients | journal = Pharmacopsychiatry | volume = 38 | issue = 4 | pages = 171–177 | date = July 2005 | pmid = 16025420 | doi = 10.1055/s-2005-871240 | url = }}