Article · Wikipedia archive · Last revised Jun 26, 2026

HPP+

HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.

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Jun 26, 2026
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HPP+
Clinical data
Other namesHaloperidol pyridinium; Haloperidol pyridinium ion; Haloperidol pyridinium cation; BCPP+; 4-CFOBP; 4-(4-Chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridinium
Drug classMonoaminergic neurotoxin
ATC code
  • None
Identifiers
  • 4-[4-(4-chlorophenyl)pyridin-1-ium-1-yl]-1-(4-fluorophenyl)butan-1-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H18ClFNO+
Molar mass354.83 g·mol−1
3D model (JSmol)
  • C1=CC(=CC=C1C2=CC=[N+](C=C2)CCCC(=O)C3=CC=C(C=C3)F)Cl
  • InChI=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
  • Key:KAPIKUHBALFONG-UHFFFAOYSA-N

HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.123

Formation and metabolism

HPP+ is formed from haloperidol, and its dehydration product HPTP, by CYP3A enzymes in the liver.124 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.12 HPP+ is a neurotoxin specifically affecting serotonergic and dopaminergic neurons, and its neurotoxicity resembles that of MPTP.2

Extrapyramidal symptoms

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.2567

Additional metabolites

Besides HPP+, another reactive metabolite of haloperidol, RHPP+, has been detected in humans.12 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

References

  1. 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.
  2. 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.
  3. 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 12 July 2025). PMID 26561842.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Ulrich S, Neuhof S, Braun V, Danos P, Pester U, Hoy L (April 2000). "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. doi:10.1097/00004714-200004000-00014. PMID 10770460.
  10. Ulrich S, Sandmann U, Genz A (July 2005). "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. doi:10.1055/s-2005-871240. PMID 16025420.