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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...

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Autores principales: Deb, Subrata, Ben-Eltriki, Mohamed, Adomat, Hans, Chin, Mei Y., Tomlinson Guns, Emma S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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