Cargando…
Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice
Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008768/ https://www.ncbi.nlm.nih.gov/pubmed/29967572 http://dx.doi.org/10.1155/2018/5849047 |
_version_ | 1783333246708219904 |
---|---|
author | Taddio, Marco F. Mu, Linjing Keller, Claudia Schibli, Roger Krämer, Stefanie D. |
author_facet | Taddio, Marco F. Mu, Linjing Keller, Claudia Schibli, Roger Krämer, Stefanie D. |
author_sort | Taddio, Marco F. |
collection | PubMed |
description | Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [(11)C]AM7 and [(11)C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([(11)C]AM7 n = 2; [(11)C]MT107, n = 4) and after administration of cyclosporine ([(11)C]MT107, n = 4). The modelling revealed a significant reduction in [(11)C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 μl/min after cyclosporine administration. The excretion profile of [(11)C]MT107 was shifted from predominantly hepatobiliary (CL(H)/CL(R) = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL(H)/CL(R) = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics. |
format | Online Article Text |
id | pubmed-6008768 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-60087682018-07-02 Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice Taddio, Marco F. Mu, Linjing Keller, Claudia Schibli, Roger Krämer, Stefanie D. Contrast Media Mol Imaging Research Article Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [(11)C]AM7 and [(11)C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([(11)C]AM7 n = 2; [(11)C]MT107, n = 4) and after administration of cyclosporine ([(11)C]MT107, n = 4). The modelling revealed a significant reduction in [(11)C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 μl/min after cyclosporine administration. The excretion profile of [(11)C]MT107 was shifted from predominantly hepatobiliary (CL(H)/CL(R) = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL(H)/CL(R) = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics. Hindawi 2018-06-03 /pmc/articles/PMC6008768/ /pubmed/29967572 http://dx.doi.org/10.1155/2018/5849047 Text en Copyright © 2018 Marco F. Taddio et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Taddio, Marco F. Mu, Linjing Keller, Claudia Schibli, Roger Krämer, Stefanie D. Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title | Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title_full | Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title_fullStr | Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title_full_unstemmed | Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title_short | Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice |
title_sort | physiologically based pharmacokinetic modelling with dynamic pet data to study the in vivo effects of transporter inhibition on hepatobiliary clearance in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008768/ https://www.ncbi.nlm.nih.gov/pubmed/29967572 http://dx.doi.org/10.1155/2018/5849047 |
work_keys_str_mv | AT taddiomarcof physiologicallybasedpharmacokineticmodellingwithdynamicpetdatatostudytheinvivoeffectsoftransporterinhibitiononhepatobiliaryclearanceinmice AT mulinjing physiologicallybasedpharmacokineticmodellingwithdynamicpetdatatostudytheinvivoeffectsoftransporterinhibitiononhepatobiliaryclearanceinmice AT kellerclaudia physiologicallybasedpharmacokineticmodellingwithdynamicpetdatatostudytheinvivoeffectsoftransporterinhibitiononhepatobiliaryclearanceinmice AT schibliroger physiologicallybasedpharmacokineticmodellingwithdynamicpetdatatostudytheinvivoeffectsoftransporterinhibitiononhepatobiliaryclearanceinmice AT kramerstefanied physiologicallybasedpharmacokineticmodellingwithdynamicpetdatatostudytheinvivoeffectsoftransporterinhibitiononhepatobiliaryclearanceinmice |