Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Leonhardt, Mirko; Keiser, Markus; Oswald, Stefan; Kühn, Jens Peter; Jia, Jia; Grube, Markus; Kroemer, Heyo K.; Siegmund, Werner; Weitschies, Werner

doi:10.1124/dmd.110.032862

Cited by 211 publications

(200 citation statements)

References 27 publications

(28 reference statements)

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“…The observed relationship between R 1 and induction of Oatp1 expression indicates that the kinetics of contrast agent uptake should give quantitative estimates of gene expression levels. Finally, because Gd 3+ -based hepatocyte-specific contrast agents have been approved for human use (15), and human OATP1B3 has been shown to take up this contrast agent (16), this could facilitate transfer of this technology to the clinic in the longer term.…”

Section: Discussionmentioning

confidence: 99%

Dual-modality gene reporter for in vivo imaging

Patrick

Hammersley

Loizou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

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The ability to track cells and their patterns of gene expression in living organisms can increase our understanding of tissue development and disease. Gene reporters for bioluminescence, fluorescence, radionuclide, and magnetic resonance imaging (MRI) have been described but these suffer variously from limited depth penetration, spatial resolution, and sensitivity. We describe here a gene reporter, based on the organic anion transporting protein Oatp1a1, which mediates uptake of a clinically approved, Gd3+-based, hepatotrophic contrast agent (gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid). Cells expressing the reporter showed readily reversible, intense, and positive contrast (up to 7.8-fold signal enhancement) in T1-weighted magnetic resonance images acquired in vivo. The maximum signal enhancement obtained so far is more than double that produced by MRI gene reporters described previously. Exchanging the Gd3+ ion for the radionuclide, 111In, also allowed detection by single-photon emission computed tomography, thus combining the spatial resolution of MRI with the sensitivity of radionuclide imaging.

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Section: Discussionmentioning

confidence: 99%

Dual-modality gene reporter for in vivo imaging

Patrick

Hammersley

Loizou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

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“…51 Therefore, uptake of Gd-BOPTA and Gd-EOB-DTPA could be inhibited by an increase in serum bilirubin levels and by inhibitors such as bromosulfophthalein and rifampicin. 52,53 In contrast, the gadolinium-labeled HDL nanoparticles we developed were taken up via HDL-receptor mediated pathways, which were not easily blocked and might more efficiently increase the contrast of the liver parenchyma. More importantly, we showed that gadolinium complexes could participate in the hepatic cholesterol metabolic pathway and be excreted into the bile, which could be of great benefit for assessing the anatomic structure and functions of the biliary tree.…”

Section: Discussionmentioning

confidence: 99%

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

Rui

Guo²,

Ding³

et al. 2012

IJN

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Background: Natural high-density lipoproteins (HDL) possess important physiological functions to the transport of cholesterol from the peripheral tissues to the liver for metabolic degradation and excretion in the bile. Methods and results:In this work, we took advantage of this pathway and prepared two different gadolinium (Gd)-DTPA-labeled cholesterol-containing recombinant HDL nanoparticles (Gd-chol-HDL) and Gd-(chol) 2 -HDL as liver-specific magnetic resonance imaging (MRI) contrast agents. The reconstituted HDL nanoparticles had structural similarity to native HDL, and could be taken up by HepG2 cells via interaction with HDL receptors in vitro. In vivo MRI studies in rats after intravenous injections of 10 µmol gadolinium per kg of recombinant HDL nanoparticles indicated that both nanoparticles could provide signal enhancement in the liver and related organs. However, different T 1 -weighted image details suggested that they participated in different cholesterol metabolism and excretion pathways in the liver. Conclusion: Such information could be highly useful to differentiate functional changes as well as anatomic differences in the liver. These cholesterol-derived contrast agents and their recombinant HDL preparations may warrant further development as a new class of contrast agents for MRI of the liver and related organs.

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“…Hepatocellular uptake of gadoxetate from blood is mediated in humans by the sinusoidal solute carriers OATP1B1, OATP1B3, and NTCP [119]. Its active secretion into bile in rats is via the apical transporter Mrp2 [120] and it is presumed that the human ortholog (MRP2) mediates its biliary excretion in humans.…”

Section: Current Clinical Use Of Gadoxetate In Liver Disease Diagnosismentioning

confidence: 99%

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

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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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 druginduced 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.

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Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Cited by 211 publications

References 27 publications

Dual-modality gene reporter for in vivo imaging

Dual-modality gene reporter for in vivo imaging

Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver

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

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