Cargando…

Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights

Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetic...

Descripción completa

Detalles Bibliográficos
Autores principales: Arora, Priyanka, Gudelsky, Gary, Desai, Pankaj B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018653/
https://www.ncbi.nlm.nih.gov/pubmed/33798227
http://dx.doi.org/10.1371/journal.pone.0248579
_version_ 1783674236289679360
author Arora, Priyanka
Gudelsky, Gary
Desai, Pankaj B.
author_facet Arora, Priyanka
Gudelsky, Gary
Desai, Pankaj B.
author_sort Arora, Priyanka
collection PubMed
description Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin®. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0–24 was 103.0 and 24.8 μg*h/ml and brain ECF AUC 0–12 was 24.0 and 4.8 μg*h/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool.
format Online
Article
Text
id pubmed-8018653
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-80186532021-04-13 Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights Arora, Priyanka Gudelsky, Gary Desai, Pankaj B. PLoS One Research Article Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin®. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0–24 was 103.0 and 24.8 μg*h/ml and brain ECF AUC 0–12 was 24.0 and 4.8 μg*h/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool. Public Library of Science 2021-04-02 /pmc/articles/PMC8018653/ /pubmed/33798227 http://dx.doi.org/10.1371/journal.pone.0248579 Text en © 2021 Arora et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Arora, Priyanka
Gudelsky, Gary
Desai, Pankaj B.
Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title_full Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title_fullStr Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title_full_unstemmed Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title_short Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights
title_sort gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: application of physiologically-based pharmacokinetic modeling to gain quantitative insights
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018653/
https://www.ncbi.nlm.nih.gov/pubmed/33798227
http://dx.doi.org/10.1371/journal.pone.0248579
work_keys_str_mv AT arorapriyanka genderbaseddifferencesinbrainandplasmapharmacokineticsofletrozoleinspraguedawleyratsapplicationofphysiologicallybasedpharmacokineticmodelingtogainquantitativeinsights
AT gudelskygary genderbaseddifferencesinbrainandplasmapharmacokineticsofletrozoleinspraguedawleyratsapplicationofphysiologicallybasedpharmacokineticmodelingtogainquantitativeinsights
AT desaipankajb genderbaseddifferencesinbrainandplasmapharmacokineticsofletrozoleinspraguedawleyratsapplicationofphysiologicallybasedpharmacokineticmodelingtogainquantitativeinsights