Reducing contrast agent residuals in hospital wastewater: the GREENWATER study protocol.

The potential enviromental impact of iodinated (ICAs) and gadolinium-based contrast agents (GBCAs) have recently come under scrutiny, considering the current nonselective wastewater treatment. However, their rapid excretion after intravenous administration could allow their potential recovery by targeting hospital sewage. The GREENWATER study aims to appraise the effective quantities of ICAs and GBCAs retrievable from patients' urine collected after computed tomography (CT) and magnetic resonance imaging (MRI) exams, selecting ICA/GBCA per-patient urinary excretion and patients' acceptance rate as study endpoints. Within a prospective, observational, single-centre, 1-year framework, we will enrol outpatients aged ≥ 18 years, scheduled to perform contrast-enhanced CT or MRI, willing to collect post-examination urine in dedicated canisters by prolonging their hospital stay to 1 h after injection. Collected urine will be processed and partially stored in the institutional biobank. Patient-based analysis will be performed for the first 100 CT and 100 MRI patients, and then, all analyses will be conducted on the pooled urinary sample. Quantification of urinary iodine and gadolinium will be performed with spectroscopy after oxidative digestion. The evaluation of the acceptance rate will assess the "environmental awareness" of patients and will aid to model how procedures to reduce ICA/GBCA enviromental impact could be adapted in different settings. Key points • Enviromental impact of iodinated and gadolinium-based contrast agents represents a growing point of attention.• Current wastewater treatment is unable to retrieve and recycle contrast agents.• Prolonging hospital stay may allow contrast agents retrieval from patients' urine.• The GREENWATER study will assess the effectively retrievable contrast agents' quantities.• The enrolment acceptance rate will allow to evaluate patients' "green sensitivity".

Microfluidic array surface ion-imprinted monolithic capillary microextraction chip on-line hyphenated with ICP-MS for the high throughput analysis of gadolinium in human body fluids.

A novel method by hyphenating chip-based array ion-imprinted monolithic microextraction with inductively coupled plasma mass spectrometry (ICP-MS) was proposed for the online analysis of trace Gd in biological samples in this work. The poly(γ-methacryloxypropyltrimethoxysilane@Gd3+-surface ion-imprinted polymer) [poly(γ-MAPS@Gd3+-SIIP)] monolithic capillary was prepared via in situ polymerization on the vinyl-modified surface of poly(γ-MAPS) using Eu3+ as the mimic template. The prepared ion-imprinted monolithic capillary possessed higher selectivity and adsorption capacity to Gd3+ than the non-imprinted monolithic capillary. Eight poly(γ-MAPS@Gd3+-SIIP) monolithic capillaries were embedded in the channels of a microfluidic chip to fabricate a chip-based array microextraction device. Factors affecting the selectivity of the prepared ion-imprinted monolithic capillary including imprinted time and the composition of the prepolymerization solution, and extraction conditions for the fabricated chip-based array ion-imprinted monolithic capillary microextraction platform were optimized. A sample throughput of 18 h-1 was achieved along with a low detection limit of 1.27 ng L-1 for Gd3+. The proposed chip-based array poly(γ-MAPS@Gd3+-SIIP) monolithic microextraction-ICP-MS method was used for the analysis of trace Gd in human urine and serum, and the recovery for spiking experiments was in the range of 88.1-96.7%. The developed integrated analysis platform possesses good interference resistance, high automation, high sensitivity and low consumption of the sample/agent, which makes it very suitable for the analysis of trace elements in complicated biological samples.

Impact of Treatment With Chelating Agents Depends on the Stability of Administered GBCAs: A Comparative Study in Rats.

OBJECTIVE: This study investigated the potential effect of the chelating agent calcium trisodium pentetate (Ca-DTPA) on the urinary excretion of gadolinium and the subsequent elimination of gadolinium (Gd) in the brain after a single intravenous administration of either a linear (gadodiamide) or a macrocyclic (gadobutrol) Gd-based contrast agent in rats. MATERIALS AND METHODS: Rats received either a single injection of gadodiamide or gadobutrol (1.8 mmol/kg, each) or saline (n = 18 per group). Seven weeks after the injection, 6 animals of each group were killed before the treatment period. From the remaining 12 animals, 6 received either 3 intravenous injections of Ca-DTPA (180 µmol/kg) or saline. Urine was collected daily for 3 days after each infusion. Gadolinium measurements by ICP-MS were performed in urine and tissue samples. RESULTS: In animals that initially received the linear gadodiamide, Ca-DTPA infusion increased the urinary excretion of Gd by a factor of 10 (cumulative amount of 114 ± 21 nmol Gd vs 10 ± 4 nmol Gd after saline infusion, P ≤ 0.0001). In contrast, animals that received the macrocyclic gadobutrol exhibited a higher spontaneous urinary excretion of Gd (33 ± 12 nmol after saline infusion) and Ca-DTPA had no impact (30 ± 11 nmol Gd, P = 0.68).The urinary excretion of Gd was associated with Gd brain content. Seven weeks after the initial Gd-based contrast agent administration, a total amount of 0.74 ± 0.053 nmol Gd was quantified in the brain after administration of gadodiamide. The Gd brain burden was partially reduced at the end of the treatment period in the animals that were repeatedly infused with Ca-DTPA (0.56 ± 0.13 nmol Gd, P = 0.009) but not with saline (0.66 ± 0.081 nmol, P = 0.32). In contrast, the total amount of macrocyclic gadobutrol measured in the brain was lower (0.11 ± 0.029 nmol Gd) and still spontaneously cleared during the 3-week saline infusion period (0.057 ± 0.019 nmol Gd (P = 0.003). Gadolinium quantified in the brain after infusions with Ca-DTPA did not differ from saline-infused animals (0.049 ± 0.014 nmol Gd). CONCLUSIONS: Administration of the chelating agent Ca-DTPA 7 weeks after injection of linear gadodiamide induced relevant urinary Gd excretion. In parallel, the Gd amount in the brain tissue decreased. This indicates a dechelated pool among the chemical Gd forms present in the rat brain after linear gadodiamide administration that can be mobilized by chelation with Ca-DTPA. In contrast, Ca-DTPA did not mobilize Gd in animals that received macrocyclic gadobutrol, indicating that the Gd measured is intact gadobutrol.

Urinary Gadolinium Levels After Contrast-Enhanced MRI in Individuals with Normal Renal Function: a Pilot Study.

INTRODUCTION: Gadolinium-based contrast agents (GBCA) have been used to enhance magnetic resonance imaging (MRI) since 1985. Recently, the media and online groups have voiced concerns about gadolinium deposition in patients with normal renal function based on "elevated" urinary gadolinium levels. The determination of increased urinary gadolinium levels is based on reference ranges developed in individuals with normal renal function who were never exposed to GBCA. Studies suggest an elevated gadolinium urinary elimination greater than 72 h post GBCA scan. We evaluated urine gadolinium concentrations over a 30-day period in patients administered GBCA. METHODS: In this prospective, observational pilot study, we enrolled subjects between 18 and 65 years of age with normal renal function who received GBCA for the first time. Urinary gadolinium was measured at days zero (prior to GBCA exposure), 3, 10, and 30 after GBCA exposure. We compared urinary gadolinium levels after GBCA exposure to the current reference range and calculated an estimated duration of "elevated" gadolinium urine levels in the average patient. RESULTS: All 13 subjects had 24-h urinary gadolinium levels higher than 0.7 µg/24 h with means of 1944 (± 1432) µg/24 h on day 3, 301 (± 218) µg/24 h on day 10, and 34 (± 33) µg/24 h on day 30. Based on calculated urinary gadolinium elimination kinetics, we estimate urinary gadolinium levels will often remain above the current reference range for > 50 days. CONCLUSION: The current reference range of 0.7 µg/24 h for 24 h urinary gadolinium is not applicable to patients for at least 30 days following GBCA exposure.

Self-identified gadolinium toxicity: comparison of gadolinium in bone and urine to healthy gadolinium-based contrast agent exposed volunteers.

OBJECTIVE: To report additional gadolinium bone and urine data that can contribute to gaps in knowledge with respect to gadolinium uptake and retention in the body. APPROACH: In vivo measurements of gadolinium retention in the tibia bone were performed on individuals self-identified as exhibiting symptoms of gadolinium toxicity as a result of receiving GBCA, as well as on control individuals. Gadolinium urine measurements for controls, symptomatic exposed, and non-symptomatic exposed were conducted through Mayo Medical Laboratories. MAIN RESULTS: Gadolinium bone concentration in the exposed group is significantly higher than the control group (p < 0.01), with a significant difference between symptomatic and non-symptomatic (p < 0.01), using a one-tailed t test on variance-weighted means. Gadolinium urine levels in both control subjects and non-symptomatic exposed subjects are significantly lower than symptomatic exposed subjects (p ≤ 0.05). A linear regression analysis for gadolinium urine levels and GBCA dose resulted in a positive linear relationship (R 2 = 0.91, p < 0.01). Gadolinium levels in urine and gadolinium concentration in bone were found to have a non-significant relationship (R 2 = 0.11, p = 0.3). SIGNIFICANCE: Significant differences in gadolinium levels in bone and urine are observed between individuals experiencing symptoms of gadolinium toxicity and for those who are not exhibiting symptoms. No correlation was observed between gadolinium in bone and gadolinium excreted in urine, suggesting that the retention of gadolinium in the body is complicated, involving multiple long-term storage sites.

Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients.

OBJECTIVES: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). MATERIALS AND METHODS: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. RESULTS: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. CONCLUSIONS: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

Gadolinium deposition disease: Initial description of a disease that has been around for a while.

PURPOSE: To describe the clinical manifestations of presumed gadolinium toxicity in patients with normal renal function. MATERIALS AND METHODS: Participants were recruited from two online gadolinium toxicity support groups. The survey was anonymous and individuals were instructed to respond to the survey only if they had evidence of normal renal function, evidence of gadolinium in their system beyond 30days of this MRI, and no pre-existent clinical symptoms and/or signs of this type. RESULTS: 42 subjects responded to the survey (age: 28-69, mean 49.1±22.4years). The most common findings were: central pain (n=15), peripheral pain (n=26), headache (n=28), and bone pain (n=26). Only subjects with distal leg and arm distribution described skin thickening (n=22). Clouded mentation and headache were the symptoms described as persistent beyond 3months in 29 subjects. Residual disease was present in all patients. Twenty-eight patients described symptoms following administration of one brand of Gadolinium-Based Contrast Agent (GBCA), 21 after a single GBCA administration and 7 after multiple GBCA administrations, including: gadopentetate dimeglumine, n=9; gadodiamide, n=4; gadoversetamide, n=4; gadobenate dimeglumine, n=4; gadobutrol, n=1; gadoteridol, n=2; and unknown, n=4. CONCLUSIONS: Gadolinium toxicity appears to arise following GBCA administration, which appears to contain clinical features seen in Nephrogenic Systemic Fibrosis, but also features not observed in that condition.

Revisiting the Pharmacokinetic Profiles of Gadolinium-Based Contrast Agents: Differences in Long-Term Biodistribution and Excretion.

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 (ß), 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.

Simple and rapid quantification of gadolinium in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF).

A simple and rapid method to determine gadolinium (Gd) concentrations in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF) was developed. With a limit of detection (LOD) of 100 µg L(-1) in urine and 80 µg L(-1) in blood plasma and a limit of quantification (LOQ) of 330 µg L(-1) in urine and 270 µg L(-1) in blood plasma, it allows analyzing urine samples taken from magnetic resonance imaging (MRI) patients during a period of up to 20 hours after the administration of Gd-based MRI contrast agents by means of TXRF. By parallel determination of the urinary creatinine concentration, it was possible to monitor the excretion kinetics of Gd from the patient's body. The Gd concentration in blood plasma samples, taken immediately after an MRI examination, could be determined after rapid and easy sample preparation by centrifugation. All measurements were validated with inductively coupled plasma mass spectrometry (ICP-MS). TXRF is considered to be an attractive alternative for fast and simple Gd analysis in human body fluids during daily routine in clinical laboratories.

Determination of gadolinium-based magnetic resonance imaging contrast agents by micellar electrokinetic capillary chromatography.

MEKC with DAD was applied to detect six Gd-based contrasting agents (CAs) (Gd-DTPA-BMA (Omniscan), Gd-HPDO3A (ProHance), Gd-DOTA (Dotarem), Gd-AAZTA, Gd-BOPTA (Multihance) and Gd-DTPA (Magnevist)) commonly used in MRI diagnostics. The achieved LODs ranged between 0.40 and 20 µM and the optimized method gave excellent precision, especially when two internal standards were applied (less than 0.34 RSD% for migration time). The MEKC technique made it possible to determine the CAs in urine and serum samples of patients having a therapeutic dose. Due to the SDS content of the running buffer, the serum samples can be directly injected to analyze Gd-based CAs without interference of high protein content.

Determination of the MRI contrast agent Gd-DTPA by SEC-ICP-MS.

The simultaneous determination of Gd(3+) and Gd-DTPA (DTPA: diethylenetriamino-pentaacetic acid), often used as contrast agent, is described. The proposed approach combines size-exclusion chromatography (SEC) and inductively coupled plasma-mass spectrometry (ICP-MS) for element-selective detection in order to determine also high-molecular Gd-complexes if present. This method was applied to the analysis of urine samples of a patient to whom Gd-DTPA was intravenously administered. The results showed that no conversion or adsorption of Gd-DTPA could be observed in any sample, even free Gd(3+) could not be detected. Urine excretion behaviour was monitored and it was proved that Gd-DTPA was almost completely (>99%) excreted by urination within one day. Traces of Gd-DTPA could be measured in hair samples, but extraction with tetramethylammonium hydroxide (TMAH) resulted in degradation of Gd-DTPA.

Pharmacokinetics and safety of gadobenate dimeglumine (multihance) in subjects with impaired liver function.

RATIONALE AND OBJECTIVES: To characterize the pharmacokinetics of gadolinium and to evaluate the safety of gadobenate dimeglumine (Gd-BOPTA) compared with placebo, in subjects with impaired liver function. METHODS: Volunteer adult subjects with hepatic impairment (Child-Pugh classification B or C) received, randomly and in double-blind fashion, either 0.1 mmol/kg gadobenate dimeglumine (n = 11) or placebo (n = 5) by intravenous injection. Blood and urine gadolinium concentrations were determined by ICP-AES and data were analyzed by compartmental and noncompartmental modeling. A full safety evaluation was performed. No magnetic resonance imaging was performed. RESULTS: A bi-exponential model fit the gadolinium blood concentration-time data for 10 of 11 subjects administered Gd-BOPTA. The mean (CV%) distribution and elimination half-lives for these subjects were 0.18 (71.9) and 2.18 (44.2) hours, respectively. Non-parametric analysis of all 11 subjects revealed a mean (CV%) area under the curve [0-inf] of 138 (41.9) microg(Gd).h/mL. Mean (CV%) values for blood clearance, steady-state volume of distribution, and renal clearance were 172 (36.0) mL/minute, 22.9 (16.7) L, and 142 (49.0) mL/minute, respectively. A mean (CV%) of approximately 80% (24.5) of the administered dose was excreted in urine during 60 to 72 hours. No safety concerns were apparent. CONCLUSION: Hepatic impairment did not modify the pharmacokinetics of gadobenate dimeglumine compared with values reported elsewhere for healthy subjects. The contrast agent was well tolerated and safe with an overall incidence of adverse events comparable to that of placebo.

High-performance liquid chromatographic determination of the magnetic resonance imaging contrast agent gadobenate ion in plasma, urine, faeces, bile and tissues.

The gadobenate ion is an intravascular paramagnetic contrast agent for magnetic resonance imaging. An HPLC method for assaying gadobenate ion in plasma, urine, faeces, bile and tissue samples is described. The analysis is based on the reversed-phase chromatographic separation of gadobenate ion from the endogenous components of biological matrices and detection by UV absorption at 210 nm. The selectivity of the method was satisfactory. The mean absolute recovery was greater than 95%. The precision and accuracy of the analytical methods were in the range 0.1-6.5% and -12 to +9.3%, respectively. The detection limits in plasma (0.1 ml), urine (0.05 ml), dried faeces (200 mg suspended in 4 ml water), bile (0.5 ml), and dried liver tissue (100 mg suspended in 1 ml water) were, respectively, 0.24, 0.47, 2.6, 0.63 and 2.8 nmol ml(-1) (corresponding to 0.16, 0.31, 1.7, 0.42 and 1.9 microg ml(-1)).

Monitoring the elimination of gadolinium-based pharmaceuticals. Cloud point preconcentration and spectrophotometric determination of Gd(III)-2-(3,5-dichloro-2-pyridylazo)-5-dimethylaminophenol in urine.

An extraction methodology based on cloud point phase separation of non-ionic surfactants has been developed for the preconcentration of ppb amounts of gadolinium in urine as a prior step to its determination by an absorptiometric procedure. A method based on the formation of complexes with 2-(3,5-dichloro-2-pyridylazo)-5-dimethylaminophenol was used for the extraction of Gd(III) in the surfactant-rich phase of non-ionic surfactant polyethyleneglycolmono-p-nonylphenylether (PONPE 7.5). The variables affecting the combined preconcentration-absorptiometric method have been evaluated and optimised. The extraction efficiency, linearity, and the limit of detection (LOD) of the method were determined. The optimised procedure was applied to determine total and free Gd(III) contents in real urine samples of patients after the NMR imaging diagnostic examination with contrast agent.

Pharmacokinetics of the liver-specific contrast agent Gd-EOB-DTPA in relation to contrast-enhanced liver imaging in humans.

This study was performed to evaluate the effect of dose on the pharmacokinetics and efficacy of the gadolinium-based contrast medium gadoxetic acid, disodium, [gadolinium (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6, 9-triazaundecandioic acid-disodium salt] (Gd-EOB-DTPA) as a liver-specific hepatobiliary contrast medium for computed tomography. Pharmacokinetics in serum and the pattern of elimination were investigated in 18 healthy volunteers up to 6 days after a 10-minute infusion of 0.2 mmol, 0.35 mmol, and 0.5 mmol of gadolinium per kilogram of body weight. Pharmacokinetic behavior was compared with the compute tomographic attenuation data in the liver parenchyma after the same doses in patients. Urinary and fecal excretion accounted for approximately equal portions of the administered dose. The degree of renal elimination increased with increasing doses, whereas renal clearance and half-life from urine data were not affected by dose. Dose-normalized area under the concentration-time curve was significantly increased with increasing doses indicating saturation in liver uptake for the highest dose. This finding was in agreement with the measured net increase in liver attenuation by computed tomography. Hepatic disposition revealed slight saturation phenomena for the highest dose (0.5 mmol gadolinium/kg). Nevertheless, this dose resulted in sufficient uptake by human liver, allowing for computed tomographic imaging.

Detection and quantitation of gadolinium chelates in human serum and urine by high-performance liquid chromatography and post-column derivatization of gadolinium with Arsenazo III.

A narrow-bore high-performance liquid chromatography method was developed for simultaneous separation of gadolinium diethylenetriaminepentaacetic acid (GdDTPA), the monomethylamide (GdDTPA-MMA) and the bis-methylamide (GdDTPA-BMA) in human serum and urine. The Gd complexes were detected at 658 nm after post-column derivatization with Arsenazo III. The serum samples were ultrafiltrated, whereas the urine samples were centrifuged and diluted before analysis. With an injection volume of 10 microliters on a 2.1 mm ID reversed-phase column, the limit of detection of GdDTPA-BMA was calculated as 0.3 microM and 1.1 microM in serum and urine, respectively. The method was validated with respect to GdDTPA-BMA with a limit of quantification set to 2 microM and 10 microM in serum and urine, respectively. The best fit of the calibration curve was obtained using non-linear regression according to the equation Y = A+BX+CX2 in the concentration ranges 2-800 microM and 10-2000 microM of GdDTPA-BMA in serum and urine, respectively. The precision of the method was found to range from 1 to 4% RSD. The recoveries of GdDTPA-BMA spiked in serum and urine were higher than 95% with an RSD equal to or less than 4%. The serum samples were stable for at least 5 months when stored at -70 degrees C, and the urine samples were stable for a least 6 months when stored at -20 degrees C.

Hepatic kinetics and magnetic resonance imaging of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid (Gd-EOB-DTPA) in dogs.

This complex study was designed to measure the transport and excretion characteristics of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid (Gd-EOB-DTPA) in dog's livers following bolus and infusion. Simultaneous T1 magnetic resonance imaging was performed to measure maximum signal enhancement. Anaesthetized dogs had cannulation of the common bile duct and urinary bladder for collections and cannulation of the femoral artery and vein for monitoring, blood sampling and infusion. Gd-EOB-DTPA was administered by bolus (range 12.5-200 mumol/kg) and infusion (range 0.4-6.4 mumol/min per kg). An hepatic transport maximum 0.09-0.15 mumol/min/kg was achieved with a blood concentration of 0.03-0.06 mumol/mL. Marked hepatic affinity for Gd-EOB-DTPA was demonstrated with measurements of liver concentration. Maximum T1 signal enhancement was achieved with blood Gd-EOB-DTPA concentration of 0.02-0.03 mumol/mL and a liver concentration of 1-2 mumol/g. The transport maximum for Gd-EOB-DTPA in the dog was similar to that for ipodate and iodipamide and effective imaging was achieved with sub-maximal doses. The maximum signal enhancement at blood concentrations less than required for maximum transport suggest a wide latitude for effective clinical imaging.

Clearance of liposomal gadolinium: in vivo decomplexation.

The contrast agents gadolinium-DTPA (diethylenetriaminepentaacetic acid), Gd-DOTA (tetraazacyclododecanetetraacetic acid), and Gd-HP-DO3A (1,4,7-tris[carboxymethyl]-10-[2' hydroxypropyl]-1,4,7,10-tetraazacyclododecane) are used in humans as extracellular contrast agents. Although free Gd+ ion is toxic, the intact Gd3+ complexes are rapidly excreted and are relatively nontoxic. Decomplexation with release of free gadolinium is a relevant clinical concern in patients with altered renal clearance. Blood pool contrast agents currently under development may have longer clearance half-lives and be more prone to decomplexation. The present study was designed to evaluate the clearance of liposomally encapsulated Gd3+ complexes (DTPA, DOTA, and HP-DO3A). The macrocyclic compounds had more rapid and complete clearance than DTPA (P less than .05). Parallel studies with carbon-14 and Gd-153-labeled complexes showed significant differences (P less than .05) in the amount of these isotopes retained in the heart, kidney, lungs, and spleen, providing strong supportive evidence for in vivo decomplexation.

Pseudolayering of Gd-DTPA in the urinary bladder.

When excreted gadolinium diethylenetriaminepentaacetic acid (DTPA) collects in the bladder of a supine patient during magnetic resonance (MR) imaging, a puzzling pattern of signal intensities is noted. A gradual change in urine signal intensity with progressive addition of Gd-DTPA does not occur; instead, three sharply defined "layers" are seen both on T1- and T2-weighted images within the urine-Gd-DTPA mixture. The physical basis for this triple-layering phenomenon was investigated. A bladder phantom was constructed to reproduce the phenomenon. T1 and T2 relaxivities of urine doped with varying concentrations of Gd-DTPA were measured in vitro; measured signal intensities corresponded closely to predicted intensities. Early urine concentrations of excreted Gd-DTPA may be relatively high (10-40 mmol/L), resulting in extremely short T1 and T2 values (less than 30 msec). These extremely short relaxation times cause an artifactual pseudolayering of signal within the urine-Gd-DTPA mixture.