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An in vitro toolbox to accelerate anti-malarial drug discovery and development

BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This wo...

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Autores principales: Charman, Susan A., Andreu, Alice, Barker, Helena, Blundell, Scott, Campbell, Anna, Campbell, Michael, Chen, Gong, Chiu, Francis C. K., Crighton, Elly, Katneni, Kasiram, Morizzi, Julia, Patil, Rahul, Pham, Thao, Ryan, Eileen, Saunders, Jessica, Shackleford, David M., White, Karen L., Almond, Lisa, Dickins, Maurice, Smith, Dennis A., Moehrle, Joerg J., Burrows, Jeremy N., Abla, Nada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941357/
https://www.ncbi.nlm.nih.gov/pubmed/31898492
http://dx.doi.org/10.1186/s12936-019-3075-5
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author Charman, Susan A.
Andreu, Alice
Barker, Helena
Blundell, Scott
Campbell, Anna
Campbell, Michael
Chen, Gong
Chiu, Francis C. K.
Crighton, Elly
Katneni, Kasiram
Morizzi, Julia
Patil, Rahul
Pham, Thao
Ryan, Eileen
Saunders, Jessica
Shackleford, David M.
White, Karen L.
Almond, Lisa
Dickins, Maurice
Smith, Dennis A.
Moehrle, Joerg J.
Burrows, Jeremy N.
Abla, Nada
author_facet Charman, Susan A.
Andreu, Alice
Barker, Helena
Blundell, Scott
Campbell, Anna
Campbell, Michael
Chen, Gong
Chiu, Francis C. K.
Crighton, Elly
Katneni, Kasiram
Morizzi, Julia
Patil, Rahul
Pham, Thao
Ryan, Eileen
Saunders, Jessica
Shackleford, David M.
White, Karen L.
Almond, Lisa
Dickins, Maurice
Smith, Dennis A.
Moehrle, Joerg J.
Burrows, Jeremy N.
Abla, Nada
author_sort Charman, Susan A.
collection PubMed
description BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D(7.4). In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
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spelling pubmed-69413572020-01-06 An in vitro toolbox to accelerate anti-malarial drug discovery and development Charman, Susan A. Andreu, Alice Barker, Helena Blundell, Scott Campbell, Anna Campbell, Michael Chen, Gong Chiu, Francis C. K. Crighton, Elly Katneni, Kasiram Morizzi, Julia Patil, Rahul Pham, Thao Ryan, Eileen Saunders, Jessica Shackleford, David M. White, Karen L. Almond, Lisa Dickins, Maurice Smith, Dennis A. Moehrle, Joerg J. Burrows, Jeremy N. Abla, Nada Malar J Research BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D(7.4). In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles. BioMed Central 2020-01-02 /pmc/articles/PMC6941357/ /pubmed/31898492 http://dx.doi.org/10.1186/s12936-019-3075-5 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
Charman, Susan A.
Andreu, Alice
Barker, Helena
Blundell, Scott
Campbell, Anna
Campbell, Michael
Chen, Gong
Chiu, Francis C. K.
Crighton, Elly
Katneni, Kasiram
Morizzi, Julia
Patil, Rahul
Pham, Thao
Ryan, Eileen
Saunders, Jessica
Shackleford, David M.
White, Karen L.
Almond, Lisa
Dickins, Maurice
Smith, Dennis A.
Moehrle, Joerg J.
Burrows, Jeremy N.
Abla, Nada
An in vitro toolbox to accelerate anti-malarial drug discovery and development
title An in vitro toolbox to accelerate anti-malarial drug discovery and development
title_full An in vitro toolbox to accelerate anti-malarial drug discovery and development
title_fullStr An in vitro toolbox to accelerate anti-malarial drug discovery and development
title_full_unstemmed An in vitro toolbox to accelerate anti-malarial drug discovery and development
title_short An in vitro toolbox to accelerate anti-malarial drug discovery and development
title_sort in vitro toolbox to accelerate anti-malarial drug discovery and development
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941357/
https://www.ncbi.nlm.nih.gov/pubmed/31898492
http://dx.doi.org/10.1186/s12936-019-3075-5
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