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The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats
BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprev...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670682/ https://www.ncbi.nlm.nih.gov/pubmed/33198812 http://dx.doi.org/10.1186/s40360-020-00456-9 |
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author | Darweesh, Ruba S. El-Elimat, Tamam Zayed, Aref Khamis, Tareq N. Babaresh, Wahby M. Arafat, Tawfiq Al Sharie, Ahmed H. |
author_facet | Darweesh, Ruba S. El-Elimat, Tamam Zayed, Aref Khamis, Tareq N. Babaresh, Wahby M. Arafat, Tawfiq Al Sharie, Ahmed H. |
author_sort | Darweesh, Ruba S. |
collection | PubMed |
description | BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. METHODS: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. RESULTS: h-GS dose significantly decreased imatinib’s C(max) and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib’s exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib’s C(max) and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib’s exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in C(max) of N-desmethyl imatinib by 71.5%. CONCLUSIONS: These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40360-020-00456-9. |
format | Online Article Text |
id | pubmed-7670682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-76706822020-11-18 The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats Darweesh, Ruba S. El-Elimat, Tamam Zayed, Aref Khamis, Tareq N. Babaresh, Wahby M. Arafat, Tawfiq Al Sharie, Ahmed H. BMC Pharmacol Toxicol Research Article BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. METHODS: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. RESULTS: h-GS dose significantly decreased imatinib’s C(max) and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib’s exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib’s C(max) and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib’s exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in C(max) of N-desmethyl imatinib by 71.5%. CONCLUSIONS: These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40360-020-00456-9. BioMed Central 2020-11-16 /pmc/articles/PMC7670682/ /pubmed/33198812 http://dx.doi.org/10.1186/s40360-020-00456-9 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Darweesh, Ruba S. El-Elimat, Tamam Zayed, Aref Khamis, Tareq N. Babaresh, Wahby M. Arafat, Tawfiq Al Sharie, Ahmed H. The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title | The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title_full | The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title_fullStr | The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title_full_unstemmed | The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title_short | The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats |
title_sort | effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, n-desmethyl imatinib, in rats |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670682/ https://www.ncbi.nlm.nih.gov/pubmed/33198812 http://dx.doi.org/10.1186/s40360-020-00456-9 |
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