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Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography

Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitabi...

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Autores principales: Hernández Lozano, Irene, Karch, Rudolf, Bauer, Martin, Blaickner, Matthias, Matsuda, Akihiro, Wulkersdorfer, Beatrix, Hacker, Marcus, Zeitlinger, Markus, Langer, Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488550/
https://www.ncbi.nlm.nih.gov/pubmed/31037511
http://dx.doi.org/10.1208/s12248-019-0323-0
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author Hernández Lozano, Irene
Karch, Rudolf
Bauer, Martin
Blaickner, Matthias
Matsuda, Akihiro
Wulkersdorfer, Beatrix
Hacker, Marcus
Zeitlinger, Markus
Langer, Oliver
author_facet Hernández Lozano, Irene
Karch, Rudolf
Bauer, Martin
Blaickner, Matthias
Matsuda, Akihiro
Wulkersdorfer, Beatrix
Hacker, Marcus
Zeitlinger, Markus
Langer, Oliver
author_sort Hernández Lozano, Irene
collection PubMed
description Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [(11)C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [(11)C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [(11)C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1208/s12248-019-0323-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-64885502019-05-17 Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography Hernández Lozano, Irene Karch, Rudolf Bauer, Martin Blaickner, Matthias Matsuda, Akihiro Wulkersdorfer, Beatrix Hacker, Marcus Zeitlinger, Markus Langer, Oliver AAPS J Research Article Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [(11)C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [(11)C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [(11)C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1208/s12248-019-0323-0) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-04-29 /pmc/articles/PMC6488550/ /pubmed/31037511 http://dx.doi.org/10.1208/s12248-019-0323-0 Text en © The Author(s) 2019 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 Article
Hernández Lozano, Irene
Karch, Rudolf
Bauer, Martin
Blaickner, Matthias
Matsuda, Akihiro
Wulkersdorfer, Beatrix
Hacker, Marcus
Zeitlinger, Markus
Langer, Oliver
Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title_full Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title_fullStr Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title_full_unstemmed Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title_short Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
title_sort towards improved pharmacokinetic models for the analysis of transporter-mediated hepatic disposition of drug molecules with positron emission tomography
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488550/
https://www.ncbi.nlm.nih.gov/pubmed/31037511
http://dx.doi.org/10.1208/s12248-019-0323-0
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