Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T.
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 ?mol/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.
Project description:Early studies suggested that Fe<sup>III</sup> complexes cannot compete with Gd<sup>III</sup> complexes as T<sub>1</sub> MRI contrast agents. Now it is shown that one member of a class of high-spin macrocyclic Fe<sup>III</sup> complexes produces more intense contrast in mice kidneys and liver at 30?minutes post-injection than does a commercially used Gd<sup>III</sup> agent and also produces similar T<sub>1</sub> relaxivity in serum phantoms at 4.7?T and 37?°C. Comparison of four different Fe<sup>III</sup> macrocyclic complexes elucidates the factors that contribute to relaxivity in?vivo including solution speciation. Variable-temperature <sup>17</sup> O NMR studies suggest that none of the complexes has a single, integral inner-sphere water that exchanges rapidly on the NMR timescale. MRI studies in mice show large in?vivo differences of three of the Fe<sup>III</sup> complexes that correspond, in part, to their r<sub>1</sub> relaxivity in phantoms. Changes in overall charge of the complex modulate contrast enhancement, especially of the kidneys.
Project description:Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (<i>K</i><sub>m,u</sub>) of gadoxetate was 106 μM (17%) (<i>n</i> = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.
Project description:Water-soluble poly(allylamine) Mn<sup>2+</sup>-doped Si (Si<sub>Mn</sub>) nanoparticles (NPs) were prepared and show promise for biologically related applications. The nanoparticles show both strong photoluminescence and good magnetic resonance contrast imaging. The morphology and average diameter were obtained through transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM); spherical crystalline Si NPs with an average diameter of 4.2 ± 0.7 nm were observed. The doping maximum obtained through this process was an average concentration of 0.4 ± 0.3% Mn per mole of Si. The water-soluble Si<sub>Mn</sub> NPs showed a strong photoluminescence with a quantum yield up to 13%. The Si<sub>Mn</sub> NPs had significant <i>T</i><sub>1</sub> contrast with an <i>r</i><sub>1</sub> relaxivity of 11.1 ± 1.5 mM<sup>-1</sup> s<sup>-1</sup> and <i>r</i><sub>2</sub> relaxivity of 32.7 ± 4.7 mM<sup>-1</sup> s<sup>-1</sup> where the concentration is in mM of Mn<sup>2+</sup>. Dextran-coated poly(allylamine) Si<sub>Mn</sub> NPs produced NPs with <i>T</i><sub>1</sub> and <i>T</i><sub>2</sub> contrast with a <i>r</i><sub>1</sub> relaxivity of 27.1 ± 2.8 mM<sup>-1</sup> s<sup>-1</sup> and <i>r</i><sub>2</sub> relaxivity of 1078.5 ± 1.9 mM<sup>-1</sup> s<sup>-1</sup>. X-band electron paramagnetic resonance spectra are fit with a two-site model demonstrating that there are two types of Mn<sup>2+</sup> in these NP's. The fits yield hyperfine splittings (<i>A</i>) of 265 and 238 MHz with significant zero field splitting (<i>D</i> and <i>E</i> terms). This is consistent with Mn in sites of symmetry lower than tetrahedral due to the small size of the NP's.
Project description:In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new Gd<sup>III</sup> complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange (<i>k</i><sub>H</sub> = 1.5 × 10<sup>11</sup> M<sup>-1</sup> s<sup>-1</sup>, <i>k</i><sub>OH</sub> = 1.7 × 10<sup>9</sup> M<sup>-1</sup> s<sup>-1</sup>). The determination of the thermodynamic stability and kinetic inertness of the Gd<sup>III</sup> complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log <i>K</i><sub>GdL</sub> = 19.26, <i>t</i><sub>1/2</sub> = 2.14 × 10<sup>7</sup> hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (<i>r</i><sub>1</sub>) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters (<i>r</i><sub>1</sub><sup>GdL1</sup> = 4.7 mM<sup>-1</sup> s<sup>-1</sup> and <i>r</i><sub>1</sub><sup>GdL2</sup> = 5.1 mM<sup>-1</sup> s<sup>-1</sup> at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the Gd<sup>III</sup> ions.
Project description:PURPOSE:Evaluate Gadoxetate Disodium enhanced dual-energy CT for visualization of perihilar cholangiocarcinoma by exploiting the hepatobiliary uptake of Gadoxetate Disodium and viewing images at the k-edge of gadolinium on the spectrum of simulated monoenergetic energies available with Dual Energy CT. MATERIAL AND METHODS:In this prospective, IRB-approved study in patients with suspected cholangiocarcinoma, subjects who underwent a clinically indicated Gadoxetate Disodium liver MRI were immediately scanned without further IV contrast administration using rapid kVp-switching dual energy CT (rsDECT). Initial Gadoxetate Disodium dose was the FDA approved clinical dose, 0.025 mmol/kg; after additional IRB/FDA approval, 10 subjects were scanned with 0.05 mmol/kg. Both 50 keV and 70 keV simulated monoenergetic images as well as gadolinium(-water) material density images were viewed qualitatively and measured quantitatively for gadolinium uptake in the hepatic parenchyma and any focal lesions identified. RESULTS:Of 18 subjects (mean age 55 years, 10M, 8F, weight 84 kg), eight were scanned with 0.025 mmol/kg (Group 1) and 10 with 0.05 mmol/kg Gadoxetate Disodium (Group 2). Five patients had cholangiocarcinoma (all in Group 1). On synthetic monoenergetic images using standard and double Gadoxetate Disodium dose, the liver parenchyma did not appear enhanced qualitatively. Comparison of mean hepatic parenchymal HU at 50 and 70 keV showed a measurable increase in attenuation at the lower viewing energy, which corresponded to the k-edge of gadolinium. No statistically significant difference was observed on quantitative gadolinium measurement of hepatic parenchyma for single versus double Gadoxetate Disodium dose using rsDECT gadolinium material density images. Of the five cholangiocarcinomas, the tumor to nontumoral hepatic tissue HU differences were 51.1 (32.2) (mean and std dev) and 49.0(26.5) at 50 and 70 keV, respectively. CONCLUSION:In this small pilot population, evaluation of potential hilar/perihilar cholangiocarcinoma using dual energy CT at both the single FDA-approved dose and double dose of gadolinium demonstrated observed differences in attenuation between the hepatic parenchyma and lesions. However, small sample size and heterogeneity of lesions warrants further investigation.
Project description:Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic.<h4>Conclusion</h4>Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.
Project description:Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.
Project description:<h4>Objectives</h4>MRI-based R2* mapping may enable reliable and rapid quantification of liver iron concentration (LIC). However, the performance and reproducibility of R2* across acquisition protocols remain unknown. Therefore, the objective of this work was to evaluate the performance and reproducibility of complex confounder-corrected R2* across acquisition protocols, at both 1.5 T and 3.0 T.<h4>Methods</h4>In this prospective study, 40 patients with suspected iron overload and 10 healthy controls were recruited with IRB approval and informed written consent and imaged at both 1.5 T and 3.0 T. For each subject, acquisitions included four different R2* mapping protocols at each field strength, and an FDA-approved R2-based method performed at 1.5 T as a reference for LIC. R2* maps were reconstructed from the complex data acquisitions including correction for noise effects and fat signal. For each subject, field strength, and R2* acquisition, R2* measurements were performed in each of the nine liver Couinaud segments and the spleen. R2* measurements were compared across protocols and field strength (1.5 T and 3.0 T), and R2* was calibrated to LIC for each acquisition and field strength.<h4>Results</h4>R2* demonstrated high reproducibility across acquisition protocols (p > 0.05 for 96/108 pairwise comparisons across 2 field strengths and 9 liver segments, ICC > 0.91 for each field strength/segment combination) and high predictive ability (AUC > 0.95 for four clinically relevant LIC thresholds). Calibration of R2* to LIC was LIC = - 0.04 + 2.62 × 10<sup>-2</sup> R2* at 1.5 T and LIC = 0.00 + 1.41 × 10<sup>-2</sup> R2* at 3.0 T.<h4>Conclusions</h4>Complex confounder-corrected R2* mapping enables LIC quantification with high reproducibility across acquisition protocols, at both 1.5 T and 3.0 T.<h4>Key points</h4>• Confounder-corrected R2* of the liver provides reproducible R2* across acquisition protocols, including different spatial resolutions, echo times, and slice orientations, at both 1.5 T and 3.0 T. • For all acquisition protocols, high correlation with R2-based liver iron concentration (LIC) quantification was observed. • The calibration between confounder-corrected R2* and LIC, at both 1.5 T and 3.0 T, is determined in this study.
Project description:The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment.We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up.Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed.