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Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4
BACKGROUND: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsy...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer International Publishing
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862537/ https://www.ncbi.nlm.nih.gov/pubmed/32888176 http://dx.doi.org/10.1007/s43440-020-00157-4 |
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author | Danek, Przemysław J. Basińska-Ziobroń, Agnieszka Wójcikowski, Jacek Daniel, Władysława A. |
author_facet | Danek, Przemysław J. Basińska-Ziobroń, Agnieszka Wójcikowski, Jacek Daniel, Władysława A. |
author_sort | Danek, Przemysław J. |
collection | PubMed |
description | BACKGROUND: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. METHODS: The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. RESULTS: The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. CONCLUSION: Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates. |
format | Online Article Text |
id | pubmed-7862537 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-78625372021-02-16 Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 Danek, Przemysław J. Basińska-Ziobroń, Agnieszka Wójcikowski, Jacek Daniel, Władysława A. Pharmacol Rep Short Communication BACKGROUND: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. METHODS: The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. RESULTS: The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. CONCLUSION: Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates. Springer International Publishing 2020-09-04 2021 /pmc/articles/PMC7862537/ /pubmed/32888176 http://dx.doi.org/10.1007/s43440-020-00157-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Short Communication Danek, Przemysław J. Basińska-Ziobroń, Agnieszka Wójcikowski, Jacek Daniel, Władysława A. Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title | Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title_full | Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title_fullStr | Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title_full_unstemmed | Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title_short | Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 |
title_sort | levomepromazine and clozapine induce the main human cytochrome p450 drug metabolizing enzyme cyp3a4 |
topic | Short Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862537/ https://www.ncbi.nlm.nih.gov/pubmed/32888176 http://dx.doi.org/10.1007/s43440-020-00157-4 |
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