A LC–MS/MS method to evaluate the hepatic uptake of the liver-specific magnetic resonance imaging contrast agent gadoxetate (Gd-EOB-DTPA) in vitro and in humans

Jia, Jia; Keiser, Markus; Nassif, Ali; Siegmund, Werner; Oswald, Stefan

doi:10.1016/j.jchromb.2012.02.014

Cited by 15 publications

(14 citation statements)

References 17 publications

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“…51 These genetic variants were also correlated with alterations in liver enhancement of MRI scans. Carriers of specific SLCO1B1*5 variants have shown a significantly reduced liver enhancement (30%–40%) of gadoxetate, indicating a loss of function compared with the wild-type transporter.…”

Section: Discussionmentioning

confidence: 94%

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging

Georgiou

Penny²,

Nicholls³

et al. 2017

Invest Radiol

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ObjectiveThe objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers.Materials and MethodsTen healthy volunteers (age range, 18–29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time.ResultsEight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes.ConclusionsThis is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.

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Section: Discussionmentioning

confidence: 94%

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging

Georgiou

Penny²,

Nicholls³

et al. 2017

Invest Radiol

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“…Before being evaluated with human subjects, the phantom was tested. The change in contrast concentration in the bottom chamber was quantitatively assessed using hydrophilic interaction chromatography (HILIC) with tandem mass spectrometry detection (LC‐MS) . For sampling, the perfusion phantom was modified by drilling three 1‐mm holes equally spaced along the bottom chamber [Fig.…”

Section: Methodsmentioning

confidence: 99%

Portable perfusion phantom for quantitative DCE‐MRI of the abdomen

et al. 2017

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Purpose To develop a portable perfusion phantom and validate its utility in quantitative dynamic contrast-enhanced magnetic resonance imaging of the abdomen. Methods A portable perfusion phantom yielding a reproducible contrast enhancement curve (CEC) was developed. A phantom package including perfusion and static phantoms were imaged simultaneously with each of three healthy human volunteers in two different 3T MR scanners. Look-up tables correlating reference (known) contrast concentrations with measured ones were created using either the static or perfusion phantom. Contrast maps of image slices showing four organs (liver, spleen, pancreas, and paravertebral muscle) were generated before and after data correction using the look-up tables. The contrast concentrations at 4.5 minutes after dosing in each of the four organs were averaged for each volunteer. The mean contrast concentrations (4 organs x 3 volunteers = 12) were compared for the two scanners, and the intra-class correlation coefficient (ICC) was calculated. Also, the ICC of the mean Ktrans values between the two scanners was calculated before and after data correction. Results The repeatability coefficient of CECs of perfusion phantom was higher than 0.997 in all measurements. The ICC of the tissue contrast concentrations between the two scanners was 0.693 before correction, but increased to 0.974 after correction using the look-up tables (LUTs) of perfusion phantom. However, the ICC was not increased after correction using static phantom (ICC: 0.617). Similarly, the ICC of the Ktrans values was 0.899 before correction, but increased to 0.996 after correction using perfusion phantom LUTs. The ICC of the Ktrans values, however, was not increased when static phantom LUTs were used (ICC: 0.866). Conclusions The perfusion phantom reduced variability in quantifying contrast concentration and Ktrans values of human abdominal tissues across different MR units, but static phantom did not. The perfusion phantom has the potential to facilitate multi-institutional clinical trials employing quantitative DCE-MRI to evaluate various abdominal malignancies.

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“…24 Competition assays were performed using OATP1A2-transfected cells with 1 mmol/L of Gd-EOB-DTPA as substrate and 0.05% to 10% of the specific OATP1A2 inhibitor polyethylene glycol 400 (PEG400; Applichem, Darmstadt, Germany). 25 Functionality of the HEK-OATP1A2 cells was ensured by using the model substance estrone 3-sulfate, whose uptake could be inhibited by naringin (data not shown).…”

Section: Affinity To Uptake Transportersmentioning

confidence: 99%

“…32,33 The uptake of Gd-EOB-DTPA in MRP2-and MRP3-containing inside-out vesicles was measured using a validated liquid chromatographyYmass spectrometry (LC-MS/MS) method. 24 In control experiments, ATP was replaced by adenosine monophosphate. Moreover, competition assays in MRP2 and MRP3 inside-out vesicles were performed using 1 mM of Gd-EOB-DTPA and MK571 or TA (Sigma-Aldrich Taufkirchen, Germany) as specific inhibitors in concentration up to 500 Kmol/L.…”

Section: Affinity To Uptake Transportersmentioning

confidence: 99%

“…Concentrations of Gd-EOB-DTPA in blood, urine, and feces were quantified using a validated LC-MS/MS assay as recently described. 9,24 Magnetic resonance imaging scan was performed with a 7-T system (ClinScan 70/30; Bruker, Ettlingen, Germany) using a rat whole-body volume coil and a fat-suppressed 3-dimensional T1-weighted gradient-echo volumetric interpolated breath-hold examination sequence (repetition time/echo time [milliseconds], 5.75/1.75; flip angle, 25 degrees; field of view, 1785 Â 963 mm; matrix, 320 Â 320 interpolated to 640 Â 640; slice thickness, 2 mm without gap) in transverse orientation. Starting with 2 measurements before contrast application, 85 measurements were performed after intravenous administration for a period of 90 minutes.…”

Section: Study Protocolmentioning

confidence: 99%

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Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid

Jia¹,

Puls

Oswald

et al. 2014

Investigative Radiology

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A LC–MS/MS method to evaluate the hepatic uptake of the liver-specific magnetic resonance imaging contrast agent gadoxetate (Gd-EOB-DTPA) in vitro and in humans

Cited by 15 publications

References 17 publications

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging

Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging

Portable perfusion phantom for quantitative DCE‐MRI of the abdomen

Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid

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