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CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes.
Life Sci. 2000 Nov 03; 67(24):2913-20.LS

Abstract

We studied the biotransformation of haloperidol, bromperidol and their reduced forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity correlated significantly with N-dealkylation rates of haloperidol and bromperidol and oxidation rates of their reduced forms, while neither ethoxyresorufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did. In chemical and immunoinhibition studies, only troleandomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorobenzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showed catalytic activity. The Vmax and Km values of N-dealkylation of bromperidol and reoxidation of reduced bromperidol were similar to those of haloperidol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to bromperidol as well as haloperidol and suggests that modification of in vivo CYP3A activity by inhibition or induction may affect the pharmacokinetics and therapeutic effects of haloperidol and bromperidol.

Authors+Show Affiliations

Tateishi T
Department of Pharmacology, St. Marianna University School of Medicine, Kanagawa, Japan. tateishi@cc.hirosaki-u.ac.jp
Watanabe M
No affiliation info available
Kumai T
No affiliation info available
Tanaka M
No affiliation info available
Moriya H
No affiliation info available
Yamaguchi S
No affiliation info available
Satoh T
No affiliation info available
Kobayashi S
No affiliation info available

MeSH

Aryl Hydrocarbon HydroxylasesBiotransformationCytochrome P-450 CYP1A2Cytochrome P-450 CYP2D6Cytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemHaloperidolHumansIn Vitro TechniquesMicrosomes, LiverMixed Function OxygenasesOxidation-ReductionOxidoreductases, N-DemethylatingPropionatesTroleandomycin

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11133003

Citation

Tateishi, T, et al. "CYP3A Is Responsible for N-dealkylation of Haloperidol and Bromperidol and Oxidation of Their Reduced Forms By Human Liver Microsomes." Life Sciences, vol. 67, no. 24, 2000, pp. 2913-20.
Tateishi T, Watanabe M, Kumai T, et al. CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes. Life Sci. 2000;67(24):2913-20.
Tateishi, T., Watanabe, M., Kumai, T., Tanaka, M., Moriya, H., Yamaguchi, S., Satoh, T., & Kobayashi, S. (2000). CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes. Life Sciences, 67(24), 2913-20.
Tateishi T, et al. CYP3A Is Responsible for N-dealkylation of Haloperidol and Bromperidol and Oxidation of Their Reduced Forms By Human Liver Microsomes. Life Sci. 2000 Nov 3;67(24):2913-20. PubMed PMID: 11133003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes. AU - Tateishi,T, AU - Watanabe,M, AU - Kumai,T, AU - Tanaka,M, AU - Moriya,H, AU - Yamaguchi,S, AU - Satoh,T, AU - Kobayashi,S, PY - 2001/1/2/pubmed PY - 2001/2/28/medline PY - 2001/1/2/entrez SP - 2913 EP - 20 JF - Life sciences JO - Life Sci VL - 67 IS - 24 N2 - We studied the biotransformation of haloperidol, bromperidol and their reduced forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity correlated significantly with N-dealkylation rates of haloperidol and bromperidol and oxidation rates of their reduced forms, while neither ethoxyresorufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did. In chemical and immunoinhibition studies, only troleandomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorobenzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showed catalytic activity. The Vmax and Km values of N-dealkylation of bromperidol and reoxidation of reduced bromperidol were similar to those of haloperidol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to bromperidol as well as haloperidol and suggests that modification of in vivo CYP3A activity by inhibition or induction may affect the pharmacokinetics and therapeutic effects of haloperidol and bromperidol. SN - 0024-3205 UR - https://www.unboundmedicine.com/medline/citation/11133003/CYP3A_is_responsible_for_N_dealkylation_of_haloperidol_and_bromperidol_and_oxidation_of_their_reduced_forms_by_human_liver_microsomes_ DB - PRIME DP - Unbound Medicine ER -