Dynamic Contrast–Enhanced MRI of OATP Dysfunction in Diabetes

Shuboni-Mulligan, Dorela; Parys, Maciej; Blanco-Fernandez, Bárbara; Mallett, Christiane L.; Schnegelberger, Regina D.; Takada, Marilia; Chakravarty, Shatadru; Hagenbuch, Bruno; Shapiro, Erik M.

doi:10.2337/db18-0525

Cited by 18 publications

(16 citation statements)

References 43 publications

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“…We previously verified that the hepatic MRI signal enhancement by Gd‐EOB‐DTPA and Gd‐BOPTA in OATP1A/1B cluster knock‐out mice was abolished relative to wild‐type FVB mice, showing the dependence of Gd‐EOB‐DTPA uptake on the OATP1A/1B transporter family . Because these mice were used to further engineer chimeric OATP1B1/1B3 knock‐in mice, the human‐mimicking hepatic MRI signal enhancement and organ clearance in the knock‐in mice is due to the presence of human OATP1B1/1B3 proteins.…”

Section: Discussionmentioning

confidence: 81%

“…Given such a large predicted effect size in the difference of the hepatic uptake of contrast agents between wild‐type mice and knock‐in mice, we determined that cohorts of 3 mice per group would be sufficient. Datasets from a previous study using OATP1A/1B cluster knockout mice from Taconic Biosciences were included in analysis . Chimeric knock‐in mice express OATP1B1/1B3 under the ApoE promoter, restricting expression to the liver.…”

Section: Methodsmentioning

confidence: 99%

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Chimeric mouse model for MRI contrast agent evaluation

Mir

Tomaszewski

Shuboni-Mulligan

et al. 2019

Magnetic Resonance in Med

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Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. Methods: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T 1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. Results: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice.Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wildtype mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts. Conclusion: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models. K E Y W O R D S chimera, gadolinium, humanized model, MRI, OATP, preclinical 388 | MIR et al.

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Section: Discussionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Chimeric mouse model for MRI contrast agent evaluation

Mir

Tomaszewski

Shuboni-Mulligan

et al. 2019

Magnetic Resonance in Med

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“…Moreover, OATP1B1 was determined to be a better reporter of Gd-BOPTA than OATP1B3 in our study. One study reported that Slco1a/1b knockout mice, which had decreased expression of OATP1A1 and OATP1B2, had significant reductions in the uptake of Gd-EOB-DTPA and Gd-BOPTA in the liver [19]. This finding suggested that OATP1A1 and OATP1B2 are primary contributors to the hepatobiliary influx of Gd-BOPTA in mice.…”

Section: Discussionmentioning

confidence: 99%

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

Lee

Hsiao

2021

IJMS

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Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.

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“…Studies in congestive rat livers [126], a rat model of advanced liver fibrosis [127] and a rat model of liver cirrhosis [128] have shown correlations between the reduced expression of rat OATP1A1 (Slco1a1) and/or MRP2 and changes in contrast enhancement in the liver. A study in a mouse model for type 2 diabetes [129] found reduced protein expression of OATP1A1 and OATP1B2 (Slco1b2) in diabetic mice, which was mirrored by reduced liver uptake of gadoxetate, suggesting a potential clinical applicability of DCE-MRI with gadoxetate in human diabetic patients. 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].…”

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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Dynamic Contrast–Enhanced MRI of OATP Dysfunction in Diabetes

Abstract: This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0525/-/DC1. M.P. is currently affiliated with the Royal (Dick) School of Veterinary Studies and the Roslin Institute, Roslin, Midlothian, U.K.

Cited by 18 publications

References 43 publications

Chimeric mouse model for MRI contrast agent evaluation

Chimeric mouse model for MRI contrast agent evaluation

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

Use of imaging to assess the activity of hepatic transporters

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