Formation of pyridinium species of haloperidol in human liver and brain

Eyles, D. W., McGrath, J. J. and Pond, S. M. (1996) Formation of pyridinium species of haloperidol in human liver and brain. Psychopharmacology, 125 3: 214-219. doi:10.1007/BF02247331

Author Eyles, D. W.
McGrath, J. J.
Pond, S. M.
Title Formation of pyridinium species of haloperidol in human liver and brain
Journal name Psychopharmacology   Check publisher's open access policy
ISSN 0033-3158
Publication date 1996-06
Sub-type Article (original research)
DOI 10.1007/BF02247331
Volume 125
Issue 3
Start page 214
End page 219
Total pages 6
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
Recent interest in the neurotoxicity of haloperidol is based on its oxidation in rodents to the pyridinium derivative, HPP+, a structural analog of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Recently, we reported that HPP+ and a newly identified reduced pyridinium, RHPP+, were present in blood and urine of haloperidol-treated schizophrenics and that the concentrations of RHPP+ exceeded those of HPP+. In this study, we examined pathways for formation of RHPP+ in subcellular fractions of human liver (n = 5) and brain (basal ganglia; n = 5). The major pathway was reduction of HPP+ (20 μM) to RHPP+ in cytosol (0.17-0.39 and 0.03-0.07 μM RHPP+/g cytosolic protein per h in liver and brain, respectively). The reactions were inhibited significantly by menadione and in brain also by daunorubicin. The inhibition profile, cytosolic location and strict NADPH dependence suggest that the enzymes involved are ketone reductases. A second pathway was oxidation of reduced haloperidol (50 μM), a major metabolite of haloperidol in blood and brain, to RHPP+. In liver microsomes, 0.17-0.63 μmol RHPP+ was formed /g microsomal protein per h. A potent inhibitor of the pathway was ketoconazole (IC50, 0.8 μM), which suggests that P-450 3A isozymes could be involved. In brain mitochondria but not microsomes, reduced haloperidol (120 μM) was oxidised to RHPP+ at a small but significant rate (0.005-0.020 μmol RHPP+/g mitochondrial protein per h) which was not attenuated by SKF 525A, quinidine, ketoconazole, or monoamine oxidase inhibitors. Further studies are warranted to establish the biological importance of these metabolites in vivo.
Keyword Drug metabolism
Brain metabolism
Human tissue
HPP+ haloperidol pyridinium derivative
RHPP(+) reduced haloperidol pyridinium derivative
Cytochrome P-450
Reduced haloperidol
Ketone reductases
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Created: Wed, 09 Mar 2011, 15:33:35 EST