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Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis
Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administ...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053955/ https://www.ncbi.nlm.nih.gov/pubmed/36976310 http://dx.doi.org/10.3390/medicines10030021 |
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author | Deb, Subrata Ben-Eltriki, Mohamed Adomat, Hans Chin, Mei Y. Tomlinson Guns, Emma S. |
author_facet | Deb, Subrata Ben-Eltriki, Mohamed Adomat, Hans Chin, Mei Y. Tomlinson Guns, Emma S. |
author_sort | Deb, Subrata |
collection | PubMed |
description | Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography–mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone. |
format | Online Article Text |
id | pubmed-10053955 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100539552023-03-30 Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis Deb, Subrata Ben-Eltriki, Mohamed Adomat, Hans Chin, Mei Y. Tomlinson Guns, Emma S. Medicines (Basel) Brief Report Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography–mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone. MDPI 2023-03-06 /pmc/articles/PMC10053955/ /pubmed/36976310 http://dx.doi.org/10.3390/medicines10030021 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Brief Report Deb, Subrata Ben-Eltriki, Mohamed Adomat, Hans Chin, Mei Y. Tomlinson Guns, Emma S. Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title | Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title_full | Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title_fullStr | Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title_full_unstemmed | Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title_short | Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis |
title_sort | effect of dexamethasone on abiraterone pharmacokinetics in mice: determined by lc/ms analysis |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053955/ https://www.ncbi.nlm.nih.gov/pubmed/36976310 http://dx.doi.org/10.3390/medicines10030021 |
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