Cargando…

Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer

PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administ...

Descripción completa

Detalles Bibliográficos
Autores principales: Brew, Christine Taylor, Blake, James F., Mistry, Anita, Liu, Fengling, Carreno, Diana, Madsen, Deidre, Mu, YongQi, Mayo, Martha, Stahl, Wilhelm, Matthews, David, Maclean, Derek, Harrison, Steve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843698/
https://www.ncbi.nlm.nih.gov/pubmed/29520505
http://dx.doi.org/10.1007/s11095-018-2356-y
_version_ 1783305120760463360
author Brew, Christine Taylor
Blake, James F.
Mistry, Anita
Liu, Fengling
Carreno, Diana
Madsen, Deidre
Mu, YongQi
Mayo, Martha
Stahl, Wilhelm
Matthews, David
Maclean, Derek
Harrison, Steve
author_facet Brew, Christine Taylor
Blake, James F.
Mistry, Anita
Liu, Fengling
Carreno, Diana
Madsen, Deidre
Mu, YongQi
Mayo, Martha
Stahl, Wilhelm
Matthews, David
Maclean, Derek
Harrison, Steve
author_sort Brew, Christine Taylor
collection PubMed
description PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R(2) = 0.7, Q(2) = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-018-2356-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5843698
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Springer US
record_format MEDLINE/PubMed
spelling pubmed-58436982018-03-19 Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer Brew, Christine Taylor Blake, James F. Mistry, Anita Liu, Fengling Carreno, Diana Madsen, Deidre Mu, YongQi Mayo, Martha Stahl, Wilhelm Matthews, David Maclean, Derek Harrison, Steve Pharm Res Research Paper PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R(2) = 0.7, Q(2) = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-018-2356-y) contains supplementary material, which is available to authorized users. Springer US 2018-03-08 2018 /pmc/articles/PMC5843698/ /pubmed/29520505 http://dx.doi.org/10.1007/s11095-018-2356-y Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Paper
Brew, Christine Taylor
Blake, James F.
Mistry, Anita
Liu, Fengling
Carreno, Diana
Madsen, Deidre
Mu, YongQi
Mayo, Martha
Stahl, Wilhelm
Matthews, David
Maclean, Derek
Harrison, Steve
Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title_full Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title_fullStr Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title_full_unstemmed Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title_short Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer
title_sort use of qspr modeling to characterize in vitro binding of drugs to a gut-restricted polymer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843698/
https://www.ncbi.nlm.nih.gov/pubmed/29520505
http://dx.doi.org/10.1007/s11095-018-2356-y
work_keys_str_mv AT brewchristinetaylor useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT blakejamesf useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT mistryanita useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT liufengling useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT carrenodiana useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT madsendeidre useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT muyongqi useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT mayomartha useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT stahlwilhelm useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT matthewsdavid useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT macleanderek useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer
AT harrisonsteve useofqsprmodelingtocharacterizeinvitrobindingofdrugstoagutrestrictedpolymer