Translation from rats to humans

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Translation from rat to human: issues and current status (conference abstract)

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Translation from rat to human

Translation from rat to human: issues and current status

by Steven Sourbron


HTN Meeting 2022

Abstract

The TRISTAN project has current completed all preclinical technical and biological validation work, and has started the process of translating methods from rats to humans. While similar methods exist and have been deployed in other liver applications, the particular focus on DILI and DDI’s poses technical constraints that require new solutions. In particular, the aim to characterize uptake rates of Gadoxetate into cells as well as the slow excretion from cells into bile requires long acquisitions – especially in the presence of strongly inhibited uptake and excretion. The aim of this talk is to sketch out the trajectory of clinical translation in TRISTAN so far and present detail on challenges encountered. 

One issue in human quantitative MRI in general is the large heterogeneity of clinical scanners by multiple vendors, the lack of standardisation in hardware and software and the fact that these are devices optimized for qualitative rather than quantitative imaging. This is in contrast to preclinical MRI scanners which are scientific instruments by definition and at higher fields are currently supplied by one single vendor. In order to estimate and help understand the impact of this scanner heterogeneity under real-world conditions of today, the first step towards clinical translation was a multi-vendor multi-site repeatability and reproducibility study of quantitative MRI in the absence of Gadoxetate [Tadimalla et al JMRI 2022]. The methodology, results and conclusions of this study will be reviewed briefly, as well as the practical experience of running them. 

The second stage towards clinical translation of the assay is an experimental medicine study in healthy volunteers, aiming to (1) derive benchmark values for Gadoxetate uptake and extraction under normal conditions and in the presence of a strong inhibitor (rifampicin), and (2) demonstrate that the effect of a strong inhibitor can be characterized reliably and consistently across subjects. Because these are the first Gadoxetate-enhanced dynamic data in humans, the study has an adaptive design allowing in the initial stages for modifications in the methodology should the data indicate the need to do so. Initially the dose of Gadoxetate for these studies is chosen at the lowest feasible value, and the study design allows this too to be stepped up if noise levels are deemed too high for reliable quantification. In this second part of the talk, I will present our first experience with the adaptive stage of the study, showing methodology and results in 3 volunteers with and without rifampicin.  

We will conclude the talk with an outlook on clinical studies that are planned in the next stage of the development.

Translation from rat to human
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Assess liver transporters in rats

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Assessment of hepatic transporter function in rats using dynamic gadoxetate-enhanced MRI: A reproducibility study (conference abstract)

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Assess reproducibility of liver transporter function

Assessment of hepatic transporter function in rats using dynamic gadoxetate-enhanced MRI: A reproducibility study 

by Catherine D. G. Hines, Sirisha Tadimalla, Claudia Green, Iina Laitinen, Ebony R. Gunwhy, Steven Sourbron, Issam Ben Khedhiri, Paul D. Hockings, Gunnar Schütz, John C. Waterton


HTN Meeting 2022.

Abstract

Background: Drug-induced perturbations of liver transporter fluxes contribute to both drug-induced liver injury and drug-drug interactions, which are significant problems in healthcare and in drug development. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using gadoxetate has been proposed for assessing liver transporter-mediated drug injury, with compartmental modelling yielding gadoxetate hepatic plasma clearance (Ktrans) and biliary efflux (kbh) rate constants as biomarkers.  

Purpose/Hypothesis: Quantify the reproducibility and repeatability of gadoxetate Ktrans and kbh in the absence of drugs and investigate robustness by comparing with the effect size of a potent inhibitor, as measured by the TRISTAN rat assay. 

Study Type: data collected from five retroprospective and eight prospective longitudinal substudies. 

Population/Subjects/Phantom/Specimen/Animal Model: 76 male Wistar-Han rats. 

Field Strength/Sequence: Two 4.7T and two 7T Bruker (Rheinstetten, Germany) scanners at three facilities using a T2-weighted (T2W) spin echo sequence for anatomy identification and a retrospectively triggered 3D Fast Low Angle Shot (FLASH) RF-spoiled gradient echo T1W acquisition. 

Assessment: 13 substudies covering three centres, two MRI field strengths, three time periods, and two substances were assessed (ndatasets=108). All 13 substudies included between three to eight rats either scanned once (baseline: Day 1) with saline or study-specific vehicle (nrats=76) or twice (follow-up, 2-7 days apart: Day 2) with saline (nrats=19) or 10 mg/kg of the strong inhibitor rifampicin (nrats=13). 

Methods: Images were analysed using a tracer kinetic (TK) two-compartment exchange model that characterises Ktrans and kbh kinetics of gadoxetate using liver ROIs with a standardised arterial input function derived from a simplified model of the rat circulation. Average Ktrans and kbh values from each study along with 95% confidence intervals were reported as the TRISTAN rat assay. From the assay, reproducibility (between-substudies) and repeatability (between-day) errors were quantified for saline data, only. Reproducibility errors were then deconstructed across centres, field strengths, and time periods to examine the relative impact of different variables. Effect sizes were calculated from data where a follow-up scan of rifampicin was acquired. One-way ANOVAs and paired T-tests were also performed, where p<0.05 was considered to be statistically significant. 

Results: Reproducibility errors were 31% and 43% for Ktrans and kbh. Differences between substudies were significant. When isolating variables, reproducibility errors were as follows for choice of (i) centre: Ktrans<26% (p=0.13), kbh<93% (p=0.03); (ii) field strength: Ktrans<16% (p=0.51), kbh<84% (p=0.34); (iii) time period: Ktrans<29% (p=0.35), kbh<54% (p=0.008). Differences between baseline and follow-up saline data were not significant, with repeatability errors (Ktrans=14+/-2%; kbh=7+/-12%) much smaller than reproducibility errors. Rifampicin significantly reduced Ktrans (-170+/-8%) and kbh (-130+/-23%) across all centres. 

Conclusion: The TRISTAN rat assay is sufficiently robust for quantifying inhibition levels over >50% in absolute or relative terms. This safely includes potent inhibitors like rifampicin (>130% inhibition). For weaker inhibitors (20%-50% inhibition) only relative changes can be measured reliably. Inhibition levels below 20% cannot be quantified. This would require further technical development to reduce the uncertainty caused by the choice of centre, field strength, and drifts over time. 

Assess liver transporters in rats: reproducibility
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Bias, Repeatability and Reproducibility of Liver T1 Mapping

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Bias, Repeatability and Reproducibility of Liver T1 Mapping With Variable Flip Angles

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REpeatability and Reproducibility of Liver T1 Mapping

Bias, Repeatability and Reproducibility of Liver T1 Mapping With Variable Flip Angles

by Sirisha Tadimalla PhD, Daniel J. Wilson PhD, David Shelley BSc, Gavin Bainbridge BSc, Margaret Saysell BSc, Iosif A. Mendichovszky MD, Martin J. Graves PhD, J. Ashley Guthrie MB, John C. Waterton PhD, Geoffrey J.M. Parker PhD, Steven P. Sourbron PhD


JMRI 2022, 56(4), 1042-1052. doi: 10.1002/jmri.28127

Abstract

Background
Three-dimensional variable flip angle (VFA) methods are commonly used for T1 mapping of the liver, but there is no data on the accuracy, repeatability, and reproducibility of this technique in this organ in a multivendor setting.

Purpose
To measure bias, repeatability, and reproducibility of VFA T1 mapping in the liver.

Study Type
Prospective observational.

Population
Eight healthy volunteers, four women, with no known liver disease.

Field Strength/Sequence
1.5-T and 3.0-T; three-dimensional steady-state spoiled gradient echo with VFAs; Look-Locker.

Assessment
Traveling volunteers were scanned twice each (30 minutes to 3 months apart) on six MRI scanners from three vendors (GE Healthcare, Philips Medical Systems, and Siemens Healthineers) at two field strengths. The maximum period between the first and last scans among all volunteers was 9 months. Volunteers were instructed to abstain from alcohol intake for at least 72 hours prior to each scan and avoid high cholesterol foods on the day of the scan.

Statistical Tests
Repeated measures ANOVA, Student t-test, Levene's test of variances, and 95% significance level. The percent error relative to literature liver T1 in healthy volunteers was used to assess bias. The relative error (RE) due to intrascanner and interscanner variation in T1 measurements was used to assess repeatability and reproducibility.

Results
The 95% confidence interval (CI) on the mean bias and mean repeatability RE of VFA T1 in the healthy liver was 34 ± 6% and 10 ± 3%, respectively. The 95% CI on the mean reproducibility RE at 1.5 T and 3.0 T was 29 ± 7% and 25 ± 4%, respectively.

Data Conclusion
Bias, repeatability, and reproducibility of VFA T1 mapping in the liver in a multivendor setting are similar to those reported for breast, prostate, and brain.

Repeatability and reproducibility of liver T1 mapping
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PBPK Modelling of PV in Rats

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Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

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PBPK Modelling of gadoxetate in rat liver

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

Daniel Scotcher, Nicola Melillo, Sirisha Tadimalla, Adam S. Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, and Aleksandra Galetin


ACS Mol. Pharmaceutics 2021, 18, 8, 2997-3009; doi:10.1021/acs.molpharmaceut.1c00206

Abstract

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug–drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro–in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis–Menten constant (Km,u) of gadoxetate was 106 μM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK–IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE–MRI profiles and elimination from the liver. Therefore, in vivo rat DCE–MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE–MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

PBPK Modelling of Gadoxetate in Rat Liver
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Liver T1 Mapping with vFA

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Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles (Conference Abstract)

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Liver T1 Mapping with vFA

Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles

Sirisha Tadimalla, Daniel Wilson, David Shelley, Gavin Bainbridge, Margaret Saysell, Iosif A Mendichovszky, Martin Graves, Geoff JM Parker, Steven Sourbron


ISMRM Conference 2021

Abstract

A multi-centre, multi-vendor study in 8 travelling healthy volunteers was conducted for technical validation of variable flip angle (VFA) T1 mapping in the liver across 6 scanners (3 vendors and 2 field strengths). The 95% CI was 28 ± 8% for the bias in liver T1, 10 ± 3% for the intra-scanner repeatability CV and 28 ± 6% for the inter-scanner reproducibility CV. These values are comparable to literature values for B1+-corrected VFA T1 in prostate, brain, breast, and phantoms. Any proposed refinement of the VFA method in the liver should demonstrate a significant improvement on those benchmarks before it can be recommended as a future standard.

Liver T1 Mapping with vFA
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Gadoxetate MRI to assess rifampicin effect

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Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI (Conference Abstract)

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Gadoxetate MRI to assess rifampicin effect

Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI

Mikael Montelius, Steven Sourbron, Nicola Melillo, Daniel Scotcher, Aleksandra Galetin, Gunnar Schuetz, Claudia Green, Edvin Johansson, John Waterton, Paul D. Hockings


ISMRM Conference 2021

Abstract

Non-invasive biomarkers for Drug Induced Liver Injury, which cause liver failure and impede drug development, and Drug-Drug Interactions affecting pharmacokinetics of drugs when combined are needed. We used gadoxetate DCE-MRI to measure clinical and high dose rifampicin effects on hepatocellular uptake in acute and chronic settings in rats. At high dose, uptake was significantly reduced after acute dosing, and returned to baseline after chronic dosing. Similar but non-significant effects was seen at clinical dose levels. We thus demonstrated the potential of gadoxetate DCE-MRI to non-invasively assess drug-induced inhibition of hepatocellular transport and DDIs. 
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Gadoxetate MRI to assess rifampicin effect
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Assess Liver Transporter Kinetics and DDI from Imaging Data

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Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate (Conference Abstract)

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Assess Liver Transporter Kinetics and DDI from Imaging Data

Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate

Daniel Scotcher

2021 Drug Metabolism Discussion Group and Swedish Academy of Pharmaceutical Sciences Online Joint Meeting

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. Quantitative prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for model validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent and substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). Gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury. The in vitro uptake kinetics of gadoxetate in plated rat hepatocytes were assessed, and transporter kinetic parameters derived using a mechanistic cell model. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence and absence of a single 10 mg/kg intravenous dose of rifampicin were used for PBPK model refinement. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding increase in gadoxetate systemic exposure in the presence of rifampicin, whereas liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile. The current study demonstrates utility of tissue imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition.
 

Assess Liver Transporter Kinetics and DDI from Imaging Data
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Imaging of DDI risk with liver transporters

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In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters (Conference Abstract)

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Imaging of DDI risk with liver transporters

In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters

J. Gerry Kenna, Claudia Green, Catherine D. G. Hines Iina Laitinen, Aleksandra Galetin, Paul D. Hockings,  Nicola Melillo, Mikael Montelius,  Daniel Scotcher, Steven Sourbron, John C. Watertone, Gunnar Schütz
 

Virtual 2021 Annual Meeting of the US Society of Toxicology and ToxExpo

Abstract

Inhibition of transporters that mediate hepatic drug uptake and/or biliary excretion may cause clinically relevant drug-drug interactions (DDIs) leading to potentiated or reduced efficacy, and/or increased or reduced toxicity to liver or other tissues. These DDIs are difficult to assess, since accurate prediction of changes in tissue exposure in vivo based on in vitro transport interaction data is challenging. Dynamic contract enhanced magnetic resonance imaging (DCE-MRI) enables in vivo visualisation of hepatic transporter mediated uptake and efflux of the contrast agent gadoxetate. When analysed using a compartmental kinetic model of gadoxetate disposition, gadoxetate DCE-MRI studies provide quantitative rate constants for hepatic gadoxetate uptake (khe) and biliary excretion (kbh). These processes are mediated primarily by Organic Anion Transport Polypeptides (OATPs) and Multidrug Resistance Protein Type 2 (MRP2), respectively. To evaluate drug effects on hepatic gadoxetate khe and kbh, DCE-MRI studies were undertaken in adult male Wistar rats (approx. 250g body weight) dosed intravenously (iv) with single doses of 
drugs (rifampicin, asunaprevir, bosentan, cyclosporin, ketoconazole, pioglitazone) that inhibited rat oatp, and human OATP, activities in vitro. Drug doses were selected, via pharmacokinetic modelling and simulation, to achieve rat peripheral blood plasma concentrations following iv administration that were equivalent to steady-state human blood plasma concentrations. Simulations predicted that the selected doses of rifampicin and cyclosporin reduced liver gadoxetate exposure in vivo, whereas the other tested drugs did not. Gadoxetate khe values were determined 20 min after iv administration of dose vehicle and then, in the same animals, after a minimum 48 hr washout interval and following drug administration (n=6 per group). Gadoxetate khe (min-1) was reduced (p < 0.01) following administration of rifampicin at 2 mg/kg (mean +SD, dose: 0.44+0.06; vehicle: 0.92+0.17) or cyclosporin at 5 mg/kg (mean+SD, dose: 0.08+0.02; vehicle: 1.00+0.24); but not after dosing of asunaprevir at 5 mg/kg, bosentan at 2 mg/kg, ketoconazole at 3 mg/kg or pioglitazone at 0.4 mg/kg. These results indicate that gadoxetate DCE-MRI may aid assessment of hepatic transporter-mediated DDI risk.

Imaging of DDI risk with liver transporters
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Proton relaxation in liver

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Survey of Water Proton Longitudinal Relaxation in Liver in vivo

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Liver longitudinal relaxation in-vivo

Survey of water proton longitudinal relaxation in liver in vivo

by John Charles Waterton


Magn Reson Mater Phy (2021). doi: 10.1007/s10334-021-00928-x

Abstract

Objective: To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature.

Methods: Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model.

Results: After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less.

Discussion: The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

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LIVER LONGITUDINAL RELAXATION IN VIVO
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Noninvasive Preclinical and Clinical Imaging of Liver

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

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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
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