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Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP.
Life Sci. 1995 Nov 17; 57(26):2439-46.LS

Abstract

The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated i.p. with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.

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Authors+Show Affiliations

Igarashi K
Faculty of Pharmaceutical Sciences, Kobegakuin University, Kobe, Japan.
Kasuya F
No affiliation info available
Fukui M
No affiliation info available
Usuki E
No affiliation info available
Castagnoli N
No affiliation info available

MeSH

AnimalsAntibodiesAntipsychotic AgentsBiotransformationBrainChromatography, High Pressure LiquidCytochrome P-450 CYP2E1Cytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InhibitorsFemaleHaloperidolInjections, IntraperitonealKetoconazoleMaleMicrosomes, LiverMitochondriaMixed Function OxygenasesNifedipinePyridinium CompoundsRatsRats, Sprague-Dawley

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8847965

Citation

Igarashi, K, et al. "Studies On the Metabolism of Haloperidol (HP): the Role of CYP3A in the Production of the Neurotoxic Pyridinium Metabolite HPP+ Found in Rat Brain Following Ip Administration of HP." Life Sciences, vol. 57, no. 26, 1995, pp. 2439-46.
Igarashi K, Kasuya F, Fukui M, et al. Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP. Life Sci. 1995;57(26):2439-46.
Igarashi, K., Kasuya, F., Fukui, M., Usuki, E., & Castagnoli, N. (1995). Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP. Life Sciences, 57(26), 2439-46.
Igarashi K, et al. Studies On the Metabolism of Haloperidol (HP): the Role of CYP3A in the Production of the Neurotoxic Pyridinium Metabolite HPP+ Found in Rat Brain Following Ip Administration of HP. Life Sci. 1995 Nov 17;57(26):2439-46. PubMed PMID: 8847965.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP. AU - Igarashi,K, AU - Kasuya,F, AU - Fukui,M, AU - Usuki,E, AU - Castagnoli,N,Jr PY - 1995/11/17/pubmed PY - 2001/3/28/medline PY - 1995/11/17/entrez SP - 2439 EP - 46 JF - Life sciences JO - Life Sci VL - 57 IS - 26 N2 - The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated i.p. with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out. SN - 0024-3205 UR - https://www.unboundmedicine.com/medline/citation/8847965/Studies_on_the_metabolism_of_haloperidol__HP_:_the_role_of_CYP3A_in_the_production_of_the_neurotoxic_pyridinium_metabolite_HPP+_found_in_rat_brain_following_ip_administration_of_HP_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0024320595022405 DB - PRIME DP - Unbound Medicine ER -