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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| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/3/896 |
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| author | Nicola Melillo Daniel Scotcher J. Gerry Kenna Claudia Green Catherine D. G. Hines Iina Laitinen Paul D. Hockings Kayode Ogungbenro Ebony R. Gunwhy Steven Sourbron John C. Waterton Gunnar Schuetz Aleksandra Galetin |
| author_facet | Nicola Melillo Daniel Scotcher J. Gerry Kenna Claudia Green Catherine D. G. Hines Iina Laitinen Paul D. Hockings Kayode Ogungbenro Ebony R. Gunwhy Steven Sourbron John C. Waterton Gunnar Schuetz Aleksandra Galetin |
| author_sort | Nicola Melillo |
| collection | DOAJ |
| 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<sub>he</sub>), and biliary excretion (k<sub>bh</sub>). 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<sub>he</sub> and k<sub>bh</sub> 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<sub>he</sub> (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. |
| first_indexed | 2024-03-11T06:02:29Z |
| format | Article |
| id | doaj.art-ad3d7aef2cea4895a8dd3d1fd0b8d311 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T06:02:29Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-ad3d7aef2cea4895a8dd3d1fd0b8d3112023-11-17T13:15:56ZengMDPI AGPharmaceutics1999-49232023-03-0115389610.3390/pharmaceutics15030896Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in RatsNicola Melillo0Daniel Scotcher1J. Gerry Kenna2Claudia Green3Catherine D. G. Hines4Iina Laitinen5Paul D. Hockings6Kayode Ogungbenro7Ebony R. Gunwhy8Steven Sourbron9John C. Waterton10Gunnar Schuetz11Aleksandra Galetin12Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Science, The University of Manchester, Manchester M13 9PL, UKCentre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Science, The University of Manchester, Manchester M13 9PL, UKBioxydyn Ltd., Manchester M15 6SZ, UKMR & CT Contrast Media Research, Bayer AG, 13353 Berlin, GermanyGSK, Collegeville, PA 19426, USASanofi-Aventis Deutschland GmbH, Bioimaging Germany, 65929 Frankfurt am Main, GermanyAntaros Medical, 431 83 Mölndal, SwedenCentre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Science, The University of Manchester, Manchester M13 9PL, UKDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TA, UKDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TA, UKBioxydyn Ltd., Manchester M15 6SZ, UKMR & CT Contrast Media Research, Bayer AG, 13353 Berlin, GermanyCentre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Science, The University of Manchester, Manchester M13 9PL, UKGadoxetate, 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<sub>he</sub>), and biliary excretion (k<sub>bh</sub>). 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<sub>he</sub> and k<sub>bh</sub> 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<sub>he</sub> (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.https://www.mdpi.com/1999-4923/15/3/896gadoxetatepharmacokineticshepatic transportersmodelling and simulationDCE-MRIOATP1B |
| spellingShingle | Nicola Melillo Daniel Scotcher J. Gerry Kenna Claudia Green Catherine D. G. Hines Iina Laitinen Paul D. Hockings Kayode Ogungbenro Ebony R. Gunwhy Steven Sourbron John C. Waterton Gunnar Schuetz Aleksandra Galetin Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats Pharmaceutics gadoxetate pharmacokinetics hepatic transporters modelling and simulation DCE-MRI OATP1B |
| 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 | gadoxetate pharmacokinetics hepatic transporters modelling and simulation DCE-MRI OATP1B |
| url | https://www.mdpi.com/1999-4923/15/3/896 |
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