Noninvasive Preclinical and Clinical Imaging of Liver

Private
Public

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

  • 151

Publications
Take a look

DILI Book Chapter

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

J. Gerry Kenna, John C. Waterton, Andreas Baudy, Aleksandra Galetin, Catherine D. G. Hines, Paul Hockings, Manishkumar Patel, Daniel Scotcher, Steven Sourbron, Sabina Ziemian and Gunnar Schuetz


In: Chen M., Will Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana Press, New York, NY doi: 10.1007/978-1-4939-7677-5_30.

 

Abstract

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and drug-induced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug−drug interactions mediated via hepatobiliary transporter perturbation.

DILI BOOK CHAPTER
Article categories

Gadoxetate relaxivities increase significantly after hepatic

Private
Public

Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

  • 149

Publications
Take a look

Conference Abstract: Gadoxetate relaxivity in liver

Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

Gregor Jost, Gunnar Schuetz, Hubertus Pietsch


ISMRM Annual Meeting 2018, 16-21 June 2018,Paris, France

 

Abstract

Gadoxetate has been clinically approved for detection and characterization of focal liver lesions by MRI. It exhibits moderate protein binding and is excreted from the body partially through the kidneys and partially by a hepatobiliary pathway. Hepatocytes take up gadoxetate mainly via OAPT and NTCP transporters and excrete it into the bile mainly utilizing Mrp2. By means of dynamic acquisition of gadoxetate signal intensity during liver uptake and excretion followed by application of a suitable kinetic model, the activity of the aforementioned liver transporters can be estimated. For kinetic modelling the gadoxetate concentration for each time point is needed which can be calculated from the signal intensity if r1 in tissue is known. In 1992 Schuhmann-Giampieri et al. reported r1 of gadoxetate to be significantly higher in liver tissue compared to blood at 0.47T. This effect has been attributed to gadoxetate’s protein binding which leads to an increased rotational correlation time. Gadoxetate relaxivities at 1.5T, 3T and 4.7T have since then been reported for water and plasma, but not for hepatocytes. We here present relaxivities for gadoxetate in hepatocytes at 1.5T and 3T to complement the original Schuhmann-Giampieri data. Measurements at 7T are in progress. Interestingly, r1 of gadoxetate after uptake into hepatocytes is about 2x higher compared to plasma and does not decrease with increasing field strength as has been shown for high relaxivity Gd based contrast agents exhibiting high protein binding e.g. gadofosveset. Gadoxetate’s higher r1 in hepatocytes has to be taken into account for pharmacokinetic modelling of dynamic gadoxetate MRI at clinical field strength, which has not been done so far.

CONFERENCE ABSTRACT: GADOXETATE RELAXIVITY IN LIVER
Article categories

Overview of the TRanslational Imaging in Drug SafeTy

Private
Public

Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

  • 148

Publications
Take a look

Conference Abstract: DILI imaging biomarkers

Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

Aleksandra Galetin, Claudia Green, Catherine Hines, Paul Hockings, Lisa Jarl, Gerry Kenna, Sascha Koehler, Iina Laitinen, Xiangjun Meng, Corin Miller, Kayode Ogungbenro, Geoff Parker, Ian Rowe, Gunnar Schuetz, Daniel Scotcher, Steven Sourbron, Klaus Strobel, Sirisha Tadimalla, Ekaterina Tankisheva, John Waterton, Sabina Ziemian


In Vivo MR Gordon Research Conference, 15-20 July 2018, Andover, NH, USA

 

Abstract

In 2017, the TRanslational Imaging in Drug SafeTy AssesmeNt (TRISTAN) Innovative Medicines Initiative (IMI) consortium commenced to leverage the potential of imaging techniques to improve drug safety analysis and translatability of findings by validating and making available imaging procedures as assays to provide biomarkers for widespread use. As such, hepatobiliary transporter assessment is being undertaken using gadoxetate-enhanced MRI-derived biomarkers. Gadoxetate is known to be a substrate for the human influx transporters OATP1B1, OATP1B3, and NTCP, and the efflux transporters MRP2 and MRP3, and their rat orthologues. These transporters contribute to relevant transporter-mediated drug-drug interactions and mediate hepatobiliary clearance of numerous drugs which cause drug-induced liver injury. In addition, inhibition of bile acid excretion by drugs is an important mechanism by which drug-induced liver injury can be initiated. In view of this, the authors seek to validate influx and efflux rates of gadoxetate as an imaging biomarker assay for in vivo liver transporter assessment.

CONFERENCE ABSTRACT: DILI IMAGING BIOMARKERS
Article categories

Slow infusion improves precision of liver function

Private
Public

Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

  • 145

Publications
Take a look

Conference Abstract: Slow infusion dce-mri

Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

Sirisha Tadimalla and Steven Sourbron


The British Chapter of ISMRM Annual Meeting, 24-26 September 2018, Somerville College, Oxford

 

Background

Quantitative dynamic contrast-enhanced (DCE) MRI with a rapidly injected bolus of gadoxetate can be used to quantify liver perfusion and transporter function [1,2]. Measuring these rapid changes requires high temporal resolution, and this involves compromises in spatial resolution, coverage or SNR. However, when the aim is to measure hepatocellular function (a slow process), rather than perfusion (a fast process), there is no rationale for a rapid injection.

CONFERENCE ABSTRACT: SLOW INFUSION DCE-MRI
Article categories

Accuracy, repeatability, and reproducibility of R1

Private
Public

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

  • 144

Publications
Take a look

Conference Abstract: Phantom R1 Repeabililty

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

JC Waterton, CDG Hines, PD Hockings, I Laitinen, S Ziemian, S Campbell, M Gottschalk, C Green, M Haase, K Hoffmann, H-P Juretschke, S Koehler, W Lloyd, Y Luo, I Mahmutovic Persson, JPB O Connor, LE Olsson, GJM Parker, K Pindoriah, JE Schneider, D Steinmann, K Strobel, I Teh, A Veltien, X Zhang, G Schuetz


British Chapter ISMRM Annual Meeting 24th-26th September 2018, Oxford, UK Poster Abstract PO-19


Background:  Many translational MR biomarkers derive from measurements of the longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.  Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days.  R1 was analysed in three different regions of interest, giving 360 measurements in total.  Root-mean-square repeatability and reproducibility coefficients of variation were calculated.  Relaxivities were calculated.  Results: Day-to-day repeatability (N=180 regions of interest) was 2.3%.  Between-centre reproducibility (N=9 centres) was 1.4%.  The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

CONFERENCE ABSTRACT: PHANTOM R1 REPEABILILTY
Article categories

Accuracy, repeatability, and reproducibility of R1 in 12

Private
Public

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

  • 137

Publications
Take a look

Conference Abstract: Accuracy of R1 determination

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

Waterton JC, Hines CDG, Hockings PD, Laitinen I, Ziemian S, Campbell S, Gottschalk M, Green C, Haase M, Hoffmann K, Juretschke H-P, Koehler S, Lloyd W, Y Luo Y, Mahmutovic Persson I, O’Connor JPB, Olsson LE, Parker GJM, Pindoria K, Schneider JE, Steinmann D, Strobel K, Teh I, Veltien A, Zhang X, Schütz G


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: ACCURACY OF R1 DETERMINATION
Article categories

Inter-site repeatability and quantitative assessment

Private
Public

Inter-site repeatability and quantitative assessment of hepatic transporter function with DCE-MRI in rats (Conference Abstract)

  • 136

Publications
Take a look

Conference Abstract: Repeatability of liver transporter function assessment

Inter-site repeatability and quantitative assessment of hepatic transporter function with DCE-MRI in rats (Conference Abstract)

Claudia Green, Sirisha Tadimalla, Denise Steinmann, Steven Sourbron, Sascha Koehler, Hans-Paul Juretschke, Iina Laitinen, John C. Waterton, Paul D. Hockings, Catherine D. G. Hines, Gunnar Schütz


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

CONFERENCE ABSTRACT: REPEATABILITY OF LIVER TRANSPORTER FUNCTION ASSESSMENT
Article categories

Repeatability and reproducibility of longitudinal relaxation rate

Private
Public

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

  • 132

Publications
Take a look

R1 repeatability and reproducibility for animal MRI

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

Waterton JC, Hines CDG, Hockings PD, Laitinen I, Ziemian S, Campbell S, Gottschalk M, Green C, Haase M, Hoffmann K, Juretschke H-P, Koehler S, Lloyd W, Y Luo Y, Mahmutovic Persson I, O’Connor JPB, Olsson LE, Parker GJM, Pindoria K, Schneider JE, Steinmann D, Strobel K, Teh I, Veltien A, Zhang X, Schütz G


Magnetic Resonance Imaging, Volume 59, June 2019, Pages 121-129 doi:10.1016/j.mri.2019.03.008

 

Abstract

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.

Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI.

Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured.

Results: CoV for day-to-day repeatability (N=180 regions of interest) was 2.34% and for between-centre reproducibility (N=9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

Interpretation: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases special care in R1-accuracy is warranted.

R1 REPEATABILITY AND REPRODUCIBILITY FOR ANIMAL MRI
Article categories

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI

Private
Public

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

  • 126

Publications
Take a look

Conference Abstract: Kinetic modelling of Gadoxetate MRI

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

Steven Sourbron


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: KINETIC MODELLING OF GADOXETATE MRI
Article categories

Clinical Gd-EOB-DTPA MRI to detect the inhibition

Private
Public

Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

  • 125

Publications
Take a look

Conference Abstract: Gadoxetate MRI to see liver transporter inhibition

Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

Sirisha Tadimalla


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: GADOXETATE MRI TO SEE LIVER TRANSPORTER INHIBITION
Article categories
Subscribe to Liver