1997 Fiscal Year Final Research Report Summary
Studies on the metabolic enzyme involved in the formation of neurotoxic pyridinium metabolite derived from antipsychotic agent
| Project/Area Number |
07672402
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | KOBEGAKUIN UNIVERSITY |
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Principal Investigator |
IGARASHI Kazuo KOBEGAKUIN UNIVERSITY Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (80098467)
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| Project Period (FY) |
1995 – 1997
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| Keywords | Haloperidol / Antipsychotic agent / Neurotoxicity / CYP3A / Cytochrome P450 / Peroxygenase / Pyridinium metabolite / Brain transportation |
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| Research Abstract |
This study was undertaken to examine the metabolic enzyme system involved in the formation neurotoxic pyridinium metabolite derived from antipsychotic agent haloperidol (HP) . The results from metabolic studies have demonstrated that HP is oxidatively converted to the pyridinium metabolite, 4- (4-chlorophenyl) -1- [4- (4-fluorophenyl) -4-oxobutyl] pyridinium species (HPP^+) , which structurally resenbles the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium species (MPP^+) . The conversion is mediated by the CYP3A isoform of cytochrome P450 in liver microsomes of animals and humans. Moreover, the results from incubation with rat brain homogenate have showned that HP is partially oxidized to pyridinium metabolite HPP^+ by peroxygenase system. HPP^+ levels in rat brain increased gradually after intraperitoneal administration of HP.In addition, in vivo microdialysis techniques revealed HPP^+ in rat brain following administration of HP.
These results suggest thst HPP^+ is not formed in the brain but also it may have been formed peripherally and then transported through the blood-brain barrier.
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