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Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats

Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarker...

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Autores principales: Melillo, Nicola, Scotcher, Daniel, Kenna, J. Gerry, Green, Claudia, Hines, Catherine D. G., Laitinen, Iina, Hockings, Paul D., Ogungbenro, Kayode, Gunwhy, Ebony R., Sourbron, Steven, Waterton, John C., Schuetz, Gunnar, Galetin, Aleksandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10057977/
https://www.ncbi.nlm.nih.gov/pubmed/36986758
http://dx.doi.org/10.3390/pharmaceutics15030896
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author Melillo, Nicola
Scotcher, Daniel
Kenna, J. Gerry
Green, Claudia
Hines, Catherine D. G.
Laitinen, Iina
Hockings, Paul D.
Ogungbenro, Kayode
Gunwhy, Ebony R.
Sourbron, Steven
Waterton, John C.
Schuetz, Gunnar
Galetin, Aleksandra
author_facet Melillo, Nicola
Scotcher, Daniel
Kenna, J. Gerry
Green, Claudia
Hines, Catherine D. G.
Laitinen, Iina
Hockings, Paul D.
Ogungbenro, Kayode
Gunwhy, Ebony R.
Sourbron, Steven
Waterton, John C.
Schuetz, Gunnar
Galetin, Aleksandra
author_sort Melillo, Nicola
collection PubMed
description Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (k(he)), and biliary excretion (k(bh)). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate k(he) and k(bh) by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in k(he) (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97–98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.
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spelling pubmed-100579772023-03-30 Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats Melillo, Nicola Scotcher, Daniel Kenna, J. Gerry Green, Claudia Hines, Catherine D. G. Laitinen, Iina Hockings, Paul D. Ogungbenro, Kayode Gunwhy, Ebony R. Sourbron, Steven Waterton, John C. Schuetz, Gunnar Galetin, Aleksandra Pharmaceutics Article Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (k(he)), and biliary excretion (k(bh)). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate k(he) and k(bh) by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in k(he) (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97–98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans. MDPI 2023-03-10 /pmc/articles/PMC10057977/ /pubmed/36986758 http://dx.doi.org/10.3390/pharmaceutics15030896 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 Article
Melillo, Nicola
Scotcher, Daniel
Kenna, J. Gerry
Green, Claudia
Hines, Catherine D. G.
Laitinen, Iina
Hockings, Paul D.
Ogungbenro, Kayode
Gunwhy, Ebony R.
Sourbron, Steven
Waterton, John C.
Schuetz, Gunnar
Galetin, Aleksandra
Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title_full Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title_fullStr Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title_full_unstemmed Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title_short Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
title_sort use of in vivo imaging and physiologically-based kinetic modelling to predict hepatic transporter mediated drug–drug interactions in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10057977/
https://www.ncbi.nlm.nih.gov/pubmed/36986758
http://dx.doi.org/10.3390/pharmaceutics15030896
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