A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function

Karageorgis, Anastassia; Lenhard, Stephen C.; Yerby, Brittany; Forsgren, Mikael; Liachenko, Serguei; Johansson, Edvin; Pilling, Mark; Peterson, Richard A.; Yang, Xi; Williams, Dominic P.; Ungersma, Sharon E.; Morgan, Ryan E.; Brouwer, Kim L. R.; Jucker, Beat M.; Hockings, Paul D.

doi:10.1371/journal.pone.0197213

Cited by 19 publications

(20 citation statements)

References 52 publications

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“…In hepatocellular carcinoma patients, one study showed an increased accumulation of gadoxetate in the tumor cells due to an increase in OATP1B1 and OATP1B3 expression and a decrease in MRP2 expression relative to healthy liver tissue [130]. DCE-MRI with gadoxetate has also been used in DDI studies in mice and rats, in which novel MRI quantification methods showed a reduction in the uptake and efflux rates of gadoxetate after treatment with rifampicin [131,132].…”

Section: Mri Contrast Agents To Study Liver Transportersmentioning

confidence: 99%

Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

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Section: Mri Contrast Agents To Study Liver Transportersmentioning

confidence: 99%

Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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“…The first approach, using what is called the Patlak model (Figure 6.4; Patlak model), uses a simple two-compartment model and estimates the gadoxetate uptake and efflux rates. The Patlak model uses an input function sampled in the blood [116,117] or spleen [118,119]. The model then assumes that the blood extracellular concentration in the liver is the same as the concentration in the blood, which is the same thing as assuming that the mean transit time och the contrast agent in the extracellular space is considered negligible.…”

Section: Patlak Modelmentioning

confidence: 99%

“…Several different studies have investigated modeling of gadoxetate-enhanced MRI as a biomarker for DILI. Initially, Ulloa et al used the Patlak model to study the effects of a hepatotoxic drug, [118] and this approach was later applied and verified in a multi-center study [119]. A similar approach was also tested by Georgiou et al [151].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Non-Invasive Characterization of Liver Disease : By Multimodal Quantitative Magnetic Resonance

Karlsson

2020

Linköping University Medical Dissertations

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There is a large and unmet need for diagnostic tool that can be used to characterize chronic liver diseases (CLD). In the earlier stages of CLD, much of the diagnostics involves performing biopsies, which are evaluated by a histopathologist for the presence of e.g. fat, iron, inflammation, and fibrosis. Performing biopsies, however, have two downsides: i) biopsies are invasive and carries a small but non-negligible risk for serious complications, ii) biopsies only represents a tiny portion of the liver and are thus prone to sampling error. Moreover, in the later stages of CLD, when the disease has progressed far enough, the ability of the liver to perform its basic function will be compromised. In this stage, there is a need for better methods for accurately measuring liver function. Additionally, measures of liver function can also be used when developing new drugs, as biomarkers for drug-induced liver injury (DILI), which is a serious drug-safety issue. Magnetic resonance imaging (MRI) is a non-invasive medical imaging modality, which have shown much promise with regards to characterizing liver disease in all of the above-mentioned aspects. The aim of this PhD project was to develop and validate MR-based methods that can be used to non-invasively characterize liver disease. Paper I investigated if R2* mapping, a MR-method for measuring liver iron content, can be confounded by liver fat. The results show fat does affect R2*. The conclusion was therefore that fat must be taken into account when measuring small amounts of liver iron, as a small increase in R2* could be due to either small amounts of iron or large amounts of fat. Paper II examined whether T1 mapping, which is another MR-method, can be used for staging liver fibrosis. The results of previous research have been mixed; some studies have been very promising, whereas other studies have been less promising. Unfortunately, the results in Paper II belongs to the less promising studies. Paper III focused on measuring liver function by dynamic contrast-enhanced MRI (DCE-MRI) using a liver specific contrast agent, which is taken up the hepatocytes and excreted to the bile. The purpose of the paper was to extend and validate a method for estimating uptake and efflux rates of the contrast agent. The method had previously only been applied in health volunteers. Paper II showed that the method can be applied to CLD patients and that the uptake of the contrast agent is lower in patients with advanced fibrosis.

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“…[5][6][7] Specific uptake of gadoxetate by hepatocytes leads to T1-shortening of liver parenchyma, while liver lesions show characteristic signal deviation from the parenchyma, thus contrasting the lesions. Genetic factors, 8 chronic liver diseases 9 and drug-drug interactions 10,11 may affect gadoxetate transport through hepatocytes, influencing liver parenchyma enhancement.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

et al. 2020

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Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3 C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol −1 s −1) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3

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A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function

Cited by 19 publications

References 52 publications

Use of imaging to assess the activity of hepatic transporters

Use of imaging to assess the activity of hepatic transporters

Non-Invasive Characterization of Liver Disease : By Multimodal Quantitative Magnetic Resonance

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

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