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Objectives: The aim of this study was to develop a method to determine hepatic and renal clearance of the 2 diastereoisomers (Gd-A, Gd-B) of Gd-EOB-DTPA separately., Materials and Methods: Between July 2017 and February 2018, 41 patients with hepatic disease were prospectively included. For each patient, 1 mL of iopromide (to determine glomerular filtration rate [GFR]) was coadministered with Gd-EOB-DTPA (Gd-A and Gd-B; 65:35 wt/wt). The plasma clearances of Gd-A (PCL-GdA) and Gd-B (PCL-GdB) as well as the iopromide (GFR) were generated by using dual plasma sampling method. Meanwhile, the patient's urine was collected for measurement of renal clearance of Gd-A (RCL-GdA) and Gd-B (RCL-GdB) to confirm its agreement with GFR. Hepatic clearances of Gd-A (HCL-GdA) and Gd-B (HCL-GdB) were calculated by subtracting the GFR from PCL-GdA and PCL-GdB, respectively, and were correlated with indocyanine green (ICG) 15 minutes retention rate (ICG R15). Pharmacokinetic parameters were compared between the two isomers and between Child-Pugh classifications using student's t test., Results: Within the group of 41 patients evaluated, both RCL-GdA and RCL-GdB demonstrated a good correlation and agreement to GFR (statistics shown in the main body). HCL-GdA demonstrated a strong negative correlation (r = -0.86, P < 0.001) with ICG R15 and was much higher than HCL-GdB (116.18 ± 75.48 vs 19.74 ± 14.24 mL/min, P < 0.001). HCL-GdB demonstrated a weak correlation (r = -0.26, P = 0.102) with ICG R15. HCL-GdA of noncirrhosis and Child-Pugh class A (151.74 ± 68.28 mL/min, n = 26) was higher than that of Child-Pugh class B (54.54 ± 39.13 mL/min, n = 15; P = 0.001)., Conclusions: A practical method was established for the determination of hepatic and renal clearance of the 2 isomers of Gd-EOB-DTPA. The 2 isomers have equal renal clearance and different hepatic clearance. The HCL-GdA may serve as a novel marker to reflect liver function reserve.

Objectives: Gadolinium-based contrast agents (GBCAs) have been used for years for magnetic resonance imaging examinations. Because of their rapid blood clearance, they were considered as very safe products until some of them were shown to induce nephrogenic systemic fibrosis in patients with renal failure and hypersignals on T1-weighted unenhanced brain scans of patients with normal renal function. To date, these adverse effects have been related almost exclusively to the use of low-stability linear agents, which are more prone to release free gadolinium. The aim of the present meta-analysis was to ascertain the existence of a deep compartment for gadolinium storage in the body and to assess whether all the GBCAs present the same toxicokinetic profile., Materials and Methods: Applying a systematic literature search methodology, all clinical and preclinical studies reporting time-dependent plasma concentrations and renal excretion data of gadolinium were identified and analyzed. Since the individual data were not available, the analysis focused on the average values per groups of subjects or animals, which had received a given GBCA at a given dose. The rate constants of the distribution phase (α), rapid elimination phase (β), and residual excretion phase (γ) of gadolinium were determined in each group from the plasma concentration (Cp) time curves and the relative urinary excretion rate (rER) time curves, taking the 2-hour time point as a reference. Moreover, as bone may represent a reservoir for long-term gadolinium accumulation and slow release into the blood stream, the time curves of the relative concentration in the bone (rCB) of Gd-labeled GBCAs in mice or rats were analyzed taking day 1 concentrations as a reference. The ratio of gadolinium concentrations in the bone marrow (CBM) as compared with the bone (CB) was also calculated., Results: The relative urinary excretion rate (rER) plots revealed a prolonged residual excretion phase of gadolinium in healthy volunteers, consistent with the existence of a deep compartment of distribution for the GBCAs. The rate constant γ of gadoterate meglumine (0.107 hour) is 5 times higher than that of the linear agents (0.020 ± 0.008 hour), indicating a much faster blood clearance for the macrocyclic GBCA. Similar results were obtained in the preclinical studies. A strong correlation was shown between the γ values of the different products and their respective thermodynamic stability constants (Ktherm). Greater clearance rates of Gd from murine bone were also found after gadoterate meglumine or gadoteridol injection (0.131-0.184 day) than after administration of the linear agents (0.004-0.067 day). The concentrations of Gd in the bone marrow (CBM) from animals exposed to either gadoterate meglumine or gadodiamide are higher than those in the bone (CB) for at least 24 hours. Moreover, the ratio of concentrations (CBM/CB) at 4 hours is significantly lower with the former agent than the latter (1.9 vs 6.5, respectively)., Conclusions: Using a nonconventional pharmacokinetic approach, we showed that gadoterate meglumine undergoes a much faster residual excretion from the body than the linear GBCAs, a process that seems related to the thermodynamic stability of the different chelates. Gadolinium dissociation occurs in vivo for some linear chelates, a mechanism that may explain their long-term retention and slow release from bone. Potential consequences in terms of bone toxicity warrant further investigations.

Objectives: The purpose of this study was to evaluate the extent to which various commercially available gadolinium-containing contrast-enhancing (CE) agents can interfere with the measurement of calcium levels by currently used laboratory methods, suggesting (spurious) hypocalcemia or hypercalcemia with a potential risk for the patient., Materials and Methods: Serum and plasma from healthy volunteers were spiked with various concentrations of 4 marketed CE agents. The calcium concentration was measured by widely used laboratory methods: the colorimetric systems Cobas Mira and Vitros 950 analyzer., Results: The measurement of calcium in serum and in plasma was not affected by the presence of gadopentetate dimeglumine (Magnevist, Schering AG, Berlin, Germany) or gadobenate dimeglumine (MultiHance, Bracco-Byk Gulden, Constance, Switzerland) in clinically relevant concentrations (up to 5 mM CE agent). Gadodiamide (Omniscan, Amersham Health, Cork, Ireland) and gadoversetamide (OptiMARK, Mallinckrodt, St. Louis, MO) did produce noticeable-and therefore potentially misleading-effects at these concentrations., Conclusions: The study demonstrates that gadopentetate dimeglumine and gadobenate dimeglumine generate no interference with colorimetric methods for calcium determination, whereas strong interference was shown for gadodiamide and gadoversetamide under clinically relevant conditions.