Abstract
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 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well‐known bias in gadoxetate rate constants. This will promote the clinical translation of MR‐based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.
Highlights
Gadoxetate (Gd-EOB-DTPA) is a clinically well-established, liver-specific, gadolinium-based contrast agent (GBCA)[1,2,3] approved for the detection and characterization of focal liver lesions by magnetic resonance imaging (MRI).[4]
We provide experimentally determined ex vivo gadoxetate r1 relaxivity values for rat liver tissue, which should approximate hepatocytes, and for blood, urine and bile across a range of magnetic field strengths from 1.41 to 7 T, relevant for both preclinical and clinical MRI scanners
We found a 2-fold higher r1 for gadoxetate in liver tissue compared with blood at 1.41 T
Summary
Gadoxetate (Gd-EOB-DTPA) is a clinically well-established, liver-specific, gadolinium-based contrast agent (GBCA)[1,2,3] approved for the detection and characterization of focal liver lesions by magnetic resonance imaging (MRI).[4]. We determined r1 numerical values for gadoxetate in liver tissue aiming at hepatocytes, in blood, urine and bile of rats ex vivo at 1.41, 1.5, 3, 4.7 and 7 T. ex vivo measurements are the only setting in which both relaxation rates and Gd concentration can be determined at the same time point in one experiment. To the homogenized hepatocyte tissue, as well as to 0.025 mL of each blood, urine and bile sample, 0.07 mL of concentrated 65% nitric acid (TraceMetal Grade, Fisher Scientific, Waltham, MA, USA) and 0.03 mL of 30% hydrogen peroxide were added to each tube. Relaxivity values were determined for blood collected 1 minute after gadoxetate injection, for urine and bile continuously collected from the time point of injection until animal sacrifice, and for liver collected 30 minutes p.i. Data from the 3 T MRI scanner and the 3 T NMR Analyzer were pooled.
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