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OBJECTIVES: Unexpected accumulations of gadolinium in various organs were reported after the administration of gadolinium-based contrast agents, making desirable to reduce the dose while maintaining equivalent diagnostic performance. The aim of this study was to evaluate the contrast enhancement performance of high relaxivity gadopiclenol compared with gadoterate meglumine in abdominal contrast-enhanced magnetic resonance angiography (CE-MRA). MATERIALS AND METHODS: In a first study in healthy rabbits, axial 3D gradient echo sequences were applied at 4.7 T to study arterial enhancement as a function of gadopiclenol dose (0.025, 0.05, 0.075, and 0.1 mmol Gd/kg) or gadoterate meglumine at 0.1 mmol Gd/kg (n = 5-6/group). The increase in signal-to-noise ratio (ΔSNR) in the aorta at the first pass was measured and compared. In a second, crossover study in 6 healthy pigs, abdominal CE-MRA sequences were acquired at 3 T with gadopiclenol at 0.05 mmol Gd/kg or gadoterate meglumine at 0.1 mmol Gd/kg at a 1-week interval. Quantitatively on the maximum intensity projection (MIP) images, the mean MIP SNR within the aorta of both groups was compared. Qualitatively, a blinded comparison of the angiograms was performed by an experienced radiologist to determine the preferred contrast agent. RESULTS: In the rabbit, ∆SNR is linearly correlated with the gadopiclenol dose ( P = 0.0010). Compared with gadoterate meglumine 0.1 mmol Gd/kg, an increase in the ∆SNR is observed after 0.05, 0.075, and 0.1 mmol Gd/kg of gadopiclenol (+63% P = 0.0731, +78% P = 0.0081, and +72% P = 0.0773, respectively), whereas at 0.025 mmol Gd/kg, ∆SNR is in the same range as with gadoterate meglumine 0.1 mmol Gd/kg (+15% P > 0.9999). In pigs, contrast enhancement after gadopiclenol at 0.05 mmol/kg is +22% superior to MIP SNR after gadoterate meglumine at 0.1 mmol Gd/kg ( P = 0.3095). Qualitatively, a preference was shown for gadopiclenol images (3/6) over the gadoterate meglumine examinations (1/6), with no preference being shown for the remainder (2/6). CONCLUSIONS: First-pass CE-MRA is feasible with gadopiclenol at 0.05 mmol Gd/kg with at least the same arterial signal enhancement and image quality as gadoterate meglumine at 0.1 mmol Gd/kg.
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Medios de Contraste , Angiografía por Resonancia Magnética , Compuestos Organometálicos , Animales , Conejos , Angiografía por Resonancia Magnética/métodos , Porcinos , Gadolinio , Aumento de la Imagen/métodos , Meglumina/análogos & derivados , Meglumina/farmacocinética , Meglumina/administración & dosificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Gadolinium-based contrast agents (GBCAs) have been used in clinical Magnetic Resonance Imaging (MRI) for more than 30 years. However, there is increasing evidence that their dissociation in vivo leads to long-term depositions of gadolinium ions in the human body. In vitro experiments provide critical insights into kinetics and thermodynamic equilibria of underlying processes, which give hints towards the in vivo situation. We developed a time-resolved MRI relaxometry-based approach that exploits distinct relaxivities of Gd3+ in different molecular environments. Its applicability to quantify the transmetallation of GBCAs, the binding of Gd3+ to competing chelators, and the combined transchelation process is demonstrated. Exemplarily, the approach is applied to investigate two representative GBCAs in the presence of Zn2+ and heparin, which is used as a model for a macromolecular and physiologically occurring chelator. Opposing indirect impacts of heparin on increasing the kinetic stability but reducing the thermodynamic stability of GBCAs are observed. The relaxivity of resulting Gd-heparin complexes is shown to be essentially increased compared to that of the parent GBCAs so that they might be one explanation for observed long-term MRI signal enhancement in vivo. In forthcoming studies, the presented method could help to identify the most potent Gd-complexing macromolecular species.
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Gadolinio DTPA/farmacocinética , Gadolinio/metabolismo , Heparina/metabolismo , Imagen por Resonancia Magnética/métodos , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Quelantes/metabolismo , Humanos , Zinc/metabolismoRESUMEN
Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.
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Hígado Graso/metabolismo , Hígado Graso/patología , Hepatocitos/metabolismo , Hepatocitos/patología , Proteínas de Transporte de Membrana/metabolismo , Obesidad/metabolismo , Obesidad/patología , Animales , Ácidos y Sales Biliares/metabolismo , Canalículos Biliares/efectos de los fármacos , Canalículos Biliares/metabolismo , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Meglumina/análogos & derivados , Meglumina/farmacocinética , Meglumina/farmacología , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Perfusión , Ratas , Ratas Zucker , Reología/efectos de los fármacosRESUMEN
Background Linear gadolinium-based contrast agents (GBCAs) are known to be retained at higher levels of gadolinium than macro-cyclic GBCAs. However, very little is known regarding their relative elimination rates and retained fraction of injected gadolinium. Purpose To quantify and compare gadolinium retention and elimination rates in human brain tissue, skin, and bone obtained from cadavers exposed to single-agent administration of either gadoteridol (macrocyclic GBCA) or gadobenate dimeglumine (linear GBCA). Materials and Methods Autopsy cases from August 2014 to July 2019 of patients exposed to a single type of GBCA, either gadoteridol or gadobenate dimeglumine, either single or multiple doses, were included. Gadolinium levels in the brain, skin, and bone were analyzed with inductively coupled plasma mass spectrometry. Linear regression was used to compare gadolinium retention between agents and estimate elimination rates of the retained gadolinium using the time between last injection and death. Results Twenty-eight cadavers with gadoteridol exposure and nine with gadobenate dimeglumine exposure were identified (22 men; age range, 19-83 years). The median gadolinium retention of gadobenate dimeglumine was 3.0-6.5 times higher than that of gadoteridol in the brain (P < .02), 4.4 times higher in bone (P = .002), and 2.9 times higher in skin (P = .05). Gadolinium retention in the globus pallidus (GP), dentate nucleus (DN), white matter (WM), bone, and skin decreased with time elapsed from last administration to death in both the gadobenate dimeglumine (GP: -3% per twofold increase in time, P = .69; DN: -2%, P = .83; WM: -20%, P = .01; bone: -22%, P = .07; skin: -47%, P < .001) and gadoteridol (GP: -17%, P = .11; DN: -16%, P = .15; WM: -30%, P < .001; bone: -11%, P = .16; skin: -24%, P = .01) groups (P values for elimination are compared with a null hypothesis of no elimination). Conclusion The linear agent gadobenate dimeglumine retains several-fold higher levels of gadolinium in the brain and bone compared with the macrocyclic agent gadoteridol. Nonzero elimination of retained gadolinium was detected in the white matter and skin for both agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.
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Compuestos Heterocíclicos/farmacocinética , Meglumina/análogos & derivados , Compuestos Organometálicos/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Huesos/metabolismo , Encéfalo/metabolismo , Cadáver , Medios de Contraste/farmacocinética , Femenino , Gadolinio/farmacocinética , Humanos , Masculino , Meglumina/farmacocinética , Persona de Mediana Edad , Piel/metabolismo , Espectrofotometría AtómicaRESUMEN
In this study, a novel rebamipide-loaded spray-dried microsphere (RSM) with enhanced drug solubility and oral bioavailability has been developed utilizing meglumine, an alkalizing agent. The influence of carriers on the drug solubility alone, and the solubility and dissolution of the drug in the RSM was investigated. Among the alkalizing agents and hydrophilic polymers tested, meglumine and polyvinyl alcohol (PVA) showed the highest drug solubility and dissolution rate, respectively. Many RSMs were manufactured with various amounts of meglumine and PVA using distilled water, and their drug solubility and dissolution were determined. The physicochemical properties, dissolution and pharmacokinetics of the chosen RSM in rats were assessed compared to the rebamipide powder and commercial tablet. Among the RSMs tested, the one composed of rebamipide, meglumine and PVA at a weight ratio of 3:1.75:6 showed the highest drug solubility and dissolution. This RSM with a smooth spherical form significantly decreased the particle size and modified the amorphous rebamipide. Furthermore, the drug solubility, dissolution, plasma concentrations, AUC and Cmax values of RSM were significantly higher than those of drug powder and commercial tablet. Thus, this RSN system developed with distilled water and meglumine is recommended as an oral water-soluble rebamipide-loaded pharmaceutical product.
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Alanina/análogos & derivados , Meglumina/síntesis química , Meglumina/farmacocinética , Microesferas , Quinolonas/síntesis química , Quinolonas/farmacocinética , Agua/química , Alanina/síntesis química , Alanina/farmacocinética , Animales , Fenómenos Químicos , Masculino , Ratas , Ratas Sprague-Dawley , Solubilidad , Difracción de Rayos X/métodosRESUMEN
BACKGROUND AND PURPOSE: Differences in molecular properties between one-molar and half-molar gadolinium-based contrast agents are thought to affect parameters obtained from dynamic contrast-enhanced imaging. The aim of our study was to investigate differences in dynamic contrast-enhanced parameters between one-molar nonionic gadobutrol and half-molar ionic gadoterate meglumine in patients with posttreatment glioma. MATERIALS AND METHODS: This prospective study enrolled 32 patients who underwent 2 20-minute dynamic contrast-enhanced examinations, one with gadobutrol and one with gadoterate meglumine. The model-free parameter of area under the signal intensity curve from 30 to 1100 seconds and the Tofts model-based pharmacokinetic parameters were calculated and compared intraindividually using paired t tests. Patients were further divided into progression (n = 12) and stable (n = 20) groups, which were compared using Student t tests. RESULTS: Gadobutrol and gadoterate meglumine did not show any significant differences in the area under the signal intensity curve or pharmacokinetic parameters of K trans, Ve, Vp, or Kep (all P > .05). Gadobutrol showed a significantly higher mean wash-in rate (0.83 ± 0.64 versus 0.29 ± 0.63, P = .013) and a significantly lower mean washout rate (0.001 ± 0.0001 versus 0.002 ± 0.002, P = .02) than gadoterate meglumine. Trends toward higher area under the curve, K trans, Ve, Vp, wash-in, and washout rates and lower Kep were observed in the progression group in comparison with the treatment-related-change group, regardless of the contrast agent used. CONCLUSIONS: Model-free and pharmacokinetic parameters did not show any significant differences between the 2 gadolinium-based contrast agents, except for a higher wash-in rate with gadobutrol and a higher washout rate with gadoterate meglumine, supporting the interchangeable use of gadolinium-based contrast agents for dynamic contrast-enhanced imaging in patients with posttreatment glioma.
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Medios de Contraste/farmacocinética , Glioma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Adulto , Anciano , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Background Despite the wide use of gadolinium-based contrast agents (GBCAs) for enhanced MRI, their neurochemical and behavioral consequences, if any, remain poorly understood. Purpose To investigate the effect of repeated exposure to a linear or macrocyclic GBCA on gadolinium retention in the central and peripheral nervous system of rats and to assess the functional implications of such retention on hippocampal neurogenesis and sensory and cognitive processing. Materials and Methods Seventy male Sprague-Dawley rats (4 weeks old) received intraperitoneal injections of gadoterate meglumine (0.6 or 2.5 mmol per kilogram of body weight), gadodiamide (0.6 or 2.5 mmol/kg), or saline daily for 20 days (February 2018-March 2019). The 5-bromo-2'-deoxyuridine injections were administered every 3 days to determine the number of proliferating cells and the number of newly maturing neurons in the hippocampus. Sensory and cognitive behavioral tests were performed to assess the effect of GBCAs on pain sensitivity and spatial working memory function, respectively. Finally, inductively coupled plasma mass spectrometry analysis was used to quantify gadolinium retention in the brain, spinal cord, and peripheral nerves 24 hours after the last GBCA administration. One-way and mixed-design analyses of variance were used for statistical analysis. Results All GBCAs resulted in significant gadolinium retention in central and peripheral nervous tissues (1.8-333.2 nmol Gd/g tissue). Pain hypersensitivity to thermal and mechanical stimuli (P < .001) was observed after gadodiamide exposure in rats but not after gadoterate meglumine exposure. Rats injected with both GBCAs showed no changes in spatial working memory or in hippocampal cell proliferation and maturation. Conclusion Gadolinium was retained in the spinal cord and peripheral nerves in rats exposed to multiple administrations of linear and macrocyclic contrast agents. Gadodiamide (linear contrast agent) but not gadoterate meglumine (macrocyclic contrast agent) led to pain hypersensitivity, but neither affected spatial working memory performance, hippocampal cellular proliferation, or hippocampal neurogenesis. © RSNA, 2020 See also the editorial by Radbruch in this issue.
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Encéfalo/efectos de los fármacos , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Imagen por Resonancia Magnética , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Percepción del Dolor/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , Cognición/efectos de los fármacos , Masculino , Neurogénesis/efectos de los fármacos , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Espectrofotometría AtómicaRESUMEN
PURPOSE: We aimed to assess the MRI findings and follow-up of multiple focal nodular hyperplasia (FNH)- like lesions in pediatric cancer patients diagnosed by imaging findings. METHODS: We retrospectively analyzed clinical data and MRI examinations of 16 pediatric patients, who had been scanned using gadoxetate disodium (n=13) and gadobenate dimeglumine (n=3). Hepatic nodules were reviewed according to their number, size, contour, T1- and T2-weighted signal intensities, arterial, portal, delayed and hepatobiliary phase enhancement patterns. Follow-up images were evaluated for nodule size, number, and appearance. RESULTS: All 16 patients received chemotherapy in due course. Time interval between the initial diagnosis of cancer and detection of the hepatic nodule was 2-14 years. Three patients had a single lesion, 13 patients had multiple nodules. The median size of the largest nodules was 19.5 mm (range, 8-41 mm). Among 16 patients that received hepatocyte-specific agents, FNH-like nodules appeared hyperintense in 11 and isointense in 5 on the hepatobiliary phase. During follow-up, increased number and size of the nodules were seen in 4 patients. The nodules showed growth between 6-15 mm. CONCLUSION: Liver MRI using hepatocyte-specific agents is a significant imaging method for the diagnosis of FNH-like lesions, which can occur in a variety of diseases. Lesions can increase in size and number in pediatric patients.
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Hiperplasia Nodular Focal/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Adolescente , Niño , Preescolar , Medios de Contraste/administración & dosificación , Quimioterapia/métodos , Femenino , Estudios de Seguimiento , Gadolinio DTPA/administración & dosificación , Gadolinio DTPA/farmacocinética , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Aumento de la Imagen/métodos , Lactante , Hígado/irrigación sanguínea , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Meglumina/administración & dosificación , Meglumina/análogos & derivados , Meglumina/farmacocinética , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , Estudios RetrospectivosRESUMEN
BACKGROUND: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized single- and multi-arm ("star") gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model. MATERIALS AND METHODS: Antibody- and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood-brain barrier was studied by fluorescent microscopy. RESULTS: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2-9.4 nm and antibody-targeted NCAs had diameters in the range 15.8-20.5 nm. Zeta potentials were in the range of -5.4--8.2 mV and -4.6--8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30-60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement. CONCLUSION: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors.
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Neoplasias Encefálicas/diagnóstico por imagen , Medios de Contraste/administración & dosificación , Glioblastoma/diagnóstico por imagen , Compuestos Heterocíclicos/administración & dosificación , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos/administración & dosificación , Animales , Línea Celular Tumoral , Medios de Contraste/química , Medios de Contraste/farmacocinética , Modelos Animales de Enfermedad , Femenino , Humanos , Meglumina/administración & dosificación , Meglumina/análogos & derivados , Meglumina/farmacocinética , Ratones Desnudos , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Compuestos Organometálicos/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Previous studies provided evidence that gadolinium can be found in the aqueous chamber (AC) of the eye several hours post injection (p.i.) of gadolinium-based contrast agents (GBCAs). This study aimed to investigate whether gadolinium can be detected promptly after injection of a macrocyclic GBCA on contrast-enhanced T1-weighted MRI in the AC of children. METHODS: This retrospective study encompassed MRI of 200 healthy eyes of children suffering from retinoblastoma of the contralateral eye. MRI was performed with an orbital coil with the children in a state of general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between pre and post contrast-enhanced T1-weighted images (Dotarem®, Guerbet, 0.1 ml/kg body weight, mean (standard deviation) p.i. time = 12:24 (± 2:31) min). RESULTS: A highly significant signal intensity increase was found in the AC of healthy eyes 12 min after GBCA injection (median ∆SIR (interquartile range) = + 0.08 (0.05-0.12), p < 0.0001). In addition, gadolinium enhancement showed a strong negative correlation with children's age in multivariate analysis with adjustment for p.i. time (p < 0.0001). CONCLUSIONS: GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between patient age and GBCA enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC. KEY POINTS: ⢠Leakage of gadolinium-based contrast agent into the aqueous chamber of infantile eyes was found promptly after intravenous injection (p < 0.0001). ⢠Gadolinium enhancement of the anterior eye chamber was negatively correlated with the children's age (p < 0.0001).
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Cámara Anterior/metabolismo , Gadolinio DTPA/farmacocinética , Imagen por Resonancia Magnética/métodos , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Neoplasias de la Retina/diagnóstico , Retinoblastoma/diagnóstico , Preescolar , Medios de Contraste/farmacocinética , Femenino , Gadolinio , Humanos , Lactante , Recién Nacido , Inyecciones Intravenosas , Masculino , Neoplasias de la Retina/metabolismo , Retinoblastoma/metabolismo , Estudios RetrospectivosRESUMEN
PURPOSE: The aim of this study was to investigate the presence and chemical forms of residual gadolinium (Gd) in rat brain after a single dose of Gd-based contrast agent. METHODS: Four groups of healthy rats (2 sacrifice time-points, n = 10/group, 80 rats in total) were randomized to receive a single intravenous injection of 1 of the 3 Gd-based contrast agents (GBCAs) (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) or the same volume of 0.9% saline solution. The injected concentration was 0.6 mmol/kg, corresponding to a concentration of 0.1 mmol/kg in humans after body surface normalization between rats and humans (according to the US Food and Drug Administration recommendations). Animals were sacrificed at 2 washout times: 1 (M1) and 5 (M5) months after the injection. Total Gd concentrations were determined in cerebellum by inductively coupled plasma mass spectrometry. Gadolinium speciation was analyzed by size-exclusion chromatography coupled to inductively coupled plasma mass spectrometry after extraction from cerebellum. RESULTS: A single injection of a clinically relevant dose of GBCA resulted in the detectable presence of Gd in the cerebellum 1 and 5 months after injection. The cerebellar total Gd concentrations after administration of the least stable GBCA (gadodiamide) were significantly higher at both time-points (M1: 0.280 ± 0.060 nmol/g; M5: 0.193 ± 0.023 nmol/g) than those observed for macrocyclic gadoterate (M1: 0.019 ± 0.004 nmol/g, M5: 0.004 ± 0.002 nmol/g; P < 0.0001). Gadolinium concentrations after injection of gadobenate were significantly lower at both time-points (M1: 0.093 ± 0.020 nmol/g; M5: 0.067 ± 0.013 nmol/g; P < 0.05) than the Gd concentration measured after injection of gadodiamide. At the 5-month time-point, the Gd concentration in the gadoterate group was also significantly lower than the Gd concentration in the gadobenate group (P < 0.05). Gadolinium speciation analysis of the water-soluble fraction showed that, after injection of the macrocyclic gadoterate, Gd was still detected only in its intact, chelated form 5 months after injection. In contrast, after a single dose of linear GBCAs (gadobenate and gadodiamide), 2 different forms were detected: intact GBCA and Gd bound to soluble macromolecules (above 80 kDa). Elimination of the intact GBCA form was also observed between the first and fifth month, whereas the amount of Gd present in the macromolecular fraction remained constant 5 months after injection. CONCLUSIONS: A single injection of a clinically relevant dose of GBCA is sufficient to investigate long-term Gd retention in the cerebellar parenchyma. Administration of linear GBCAs (gadodiamide and gadobenate) resulted in higher residual Gd concentrations than administration of the macrocyclic gadoterate. Speciation analysis of the water-soluble fraction of cerebellum confirmed washout of intact GBCA over time. The quantity of Gd bound to macromolecules, observed only with linear GBCAs, remained constant 5 months after injection and is likely to represent a permanent deposition.
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Encéfalo/metabolismo , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Gadolinio/farmacocinética , Meglumina/análogos & derivados , Compuestos Organometálicos/farmacocinética , Animales , Cromatografía en Gel , Medios de Contraste/administración & dosificación , Femenino , Gadolinio/administración & dosificación , Gadolinio DTPA/administración & dosificación , Humanos , Inyecciones Intravenosas , Meglumina/administración & dosificación , Meglumina/farmacocinética , Modelos Animales , Compuestos Organometálicos/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: The signal enhancement (SE) and enhancement kinetics of gadolinium-based contrast agents (GBCAs) in T1-weighted magnetic resonance (MR) images depend on the relaxivity of the GBCA and its pharmacokinetic profile. This in vivo study systematically compared the SE (technical efficacy) and the enhancement kinetics of the 3 macrocyclic GBCAs gadobutrol, gadoteridol, and gadoterate meglumine in various body regions. MATERIALS AND METHODS: A total of 15 healthy male white New Zealand rabbits were randomly divided into 3 groups (n = 5/group). The GBCAs were injected intravenously (0.1 mmol/kg body weight) and signal intensities from multiphase T1-weighted MR images (1.5 T; volumetric interpolated breath-hold examination (VIBE); repetition time/echo time/α: 4.74 milliseconds/2.38 milliseconds/10°) before and up to approximately 23 minutes after contrast injection were determined in the brain, tongue, submandibular gland, liver, spleen, prostate, muscle, and blood/aorta). Thirty minutes after injection, the animals were sacrificed and Gadolinium (Gd) concentrations were determined in the above-mentioned tissue samples by inductively coupled plasma optical emission spectrometry. Gadolinium tissue concentrations were correlated with the respective SE measurements in each tissue. RESULTS: The time course of SE, representing the pharmacokinetic profile of the GBCA, was similar for all 3 agents in all tissues. The magnitude of SE was, however, tissue dependent and consistently higher for gadobutrol (P < 0.05 in all tissues but brain). No significant difference in the magnitude of SE was found between gadoteridol and gadoterate meglumine. The inductively coupled plasma optical emission spectrometry analysis revealed no differences in Gd-tissue concentrations between the GBCAs. A linear correlation was observed between SE and the respective Gd concentrations for all 3 GBCAs. A significantly higher enhancement efficacy, that is, SE per Gd concentration, was observed for gadobutrol. CONCLUSIONS: Gadobutrol-enhanced MR imaging showed greater SE compared with gadoteridol and gadoterate meglumine, whereas the SE kinetics were similar among the 3 GBCAs. For all 3 GBCAs, the SE was independent of the body region.
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Encéfalo/diagnóstico por imagen , Compuestos Heterocíclicos/farmacocinética , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Próstata/diagnóstico por imagen , Animales , Encéfalo/metabolismo , Medios de Contraste/farmacocinética , Gadolinio/farmacocinética , Humanos , Inyecciones Intravenosas , Hígado/metabolismo , Masculino , Modelos Animales , ConejosRESUMEN
OBJECTIVES: Being administered intravenously, the tissue that gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging mostly encounter is blood. Herein, it has been investigated how much Gd is internalized by cellular blood components upon the in vitro incubation of GBCAs in human blood or upon intravenous administration of GBCAs to healthy mice. We report results that show how the superb sensitivity of inductively coupled plasma-mass spectrometry (ICP-MS) allows the detection of very tiny amounts of GBCAs entering red blood cells (RBCs) and white blood cells (WBCs). This finding may introduce new insights in the complex matter relative to excretion and retention pathway of administered GBCAs. MATERIALS AND METHODS: The study was tackled by 2 independent approaches. First, human blood was incubated in vitro with 5 mM of GBCAs (gadoteridol, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine) for variable times (30 minutes, 1 hour, 2 hours, and 3 hours) at 37°C. Then, blood cell components were isolated by using the Ficoll Histopaque method, washed 3 times, mineralized, and analyzed by ICP-MS for total Gd quantification. Furthermore, blood components derived from human blood incubated with gadodiamide or gadoteridol underwent UPLC-MS (ultra performance liquid chromatography-mass spectrometry) analysis for determination of the amount of intact Gd-DTPA-BMA and Gd-HPDO3A. Second, the distribution of Gd in the blood components of healthy CD-1 mice was administered intravenously with a single dose (1.2 mmol/kg) of gadodiamide or gadoteridol. Blood samples were separated and processed at different time points (24 hours, 48 hours, 96 hours, and 10 days after GBCA administration). As for human blood, ICP-MS quantification of total Gd and UPLC-MS determination of the amount of intact GBCAs were carried out. RESULTS: The amount of Gd taken up by RBCs and WBCs was well detectable by ICP-MS. The GBCAs seem to be able to cross the membrane by diffusion (RBCs) or, possibly, by macropinocytosis (WBCs). Ex vivo studies allowed it to be established that the structure of the different GBCAs were not relevant to determine the amount of Gd internalized in the cells. Although the amount of Gd steadily decreases over time in gadoteridol-labeled cells, in the case of gadodiamide, the amount of Gd in the cells does not decrease (even 10 days after the administration of the GBCA). Moreover, while gadoteridol maintains its structural integrity upon cellular uptake, in the case of gadodiamide, the amount of intact complex markedly decreases over time. CONCLUSIONS: The detection of significant amounts of Gd in RBCs and WBCs indicates that GBCAs can cross blood cell membranes. This finding may play a role in our understanding of the processes that are at the basis of Gd retention in the tissues of patients who have received the administration of GBCAs.
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Medios de Contraste/farmacocinética , Eritrocitos/metabolismo , Gadolinio/farmacocinética , Leucocitos/metabolismo , Imagen por Resonancia Magnética , Animales , Medios de Contraste/administración & dosificación , Gadolinio/administración & dosificación , Gadolinio DTPA/administración & dosificación , Gadolinio DTPA/farmacocinética , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacocinética , Humanos , Técnicas In Vitro , Masculino , Meglumina/administración & dosificación , Meglumina/análogos & derivados , Meglumina/farmacocinética , Ratones , Modelos Animales , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , Espectrofotometría Atómica/métodosRESUMEN
Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the diffusion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabilization. Three compounds were tested (MultiHance, Gadovist, and Dotarem). We characterized their diffusion through in vivo experimental tests supported by theoretical models. Specifically, by estimation of the free diffusion coefficients from in vitro studies and of apparent diffusion coefficients from in vivo experiments, we have assessed tortuosity in the right striatum of 9 Sprague Dawley rats through a model correctly describing both vascular permeability as a function of time and diffusion processes occurring in the brain tissue. This model takes into account acoustic pressure, particle size, blood pharmacokinetics, and diffusion rates. Our model is able to fully predict the result of a FUS-induced BBB opening experiment at long space and time scales. Recovered values of tortuosity are in agreement with the literature and demonstrate that our improved model allows us to assess that the chosen permeabilization protocol preserves the integrity of the brain tissue.
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Barrera Hematoencefálica/diagnóstico por imagen , Permeabilidad Capilar , Medios de Contraste/farmacocinética , Cuerpo Estriado/diagnóstico por imagen , Compuestos Heterocíclicos/farmacocinética , Meglumina/análogos & derivados , Microburbujas , Nanoconjugados , Compuestos Organometálicos/farmacocinética , Fosfolípidos/farmacocinética , Hexafluoruro de Azufre/farmacocinética , Ondas Ultrasónicas , Algoritmos , Animales , Barrera Hematoencefálica/efectos de la radiación , Cuerpo Estriado/metabolismo , Difusión , Espacio Extracelular , Masculino , Meglumina/farmacocinética , Nanoconjugados/química , Tamaño de la Partícula , Fantasmas de Imagen , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Excretion of cardiovascular magnetic resonance (CMR) extracellular gadolinium-based contrast agents (GBCA) into pleural and pericardial effusions, sometimes referred to as vicarious excretion, has been described as a rare occurrence using T1-weighted imaging. However, the T1 mapping characteristics as well as presence, magnitude and dynamics of contrast excretion into these effusions is not known. AIMS: To investigate and compare the differences in T1 mapping characteristics and extracellular GBCA excretion dynamics in pleural and pericardial effusions. METHODS: Clinically referred patients with a pericardial and/or pleural effusion underwent CMR T1 mapping at 1.5 T before, and at 3 (early) and at 27 (late) minutes after administration of an extracellular GBCA (0.2 mmol/kg, gadoteric acid). Analyzed effusion characteristics were native T1, ΔR1 early and late after contrast injection, and the effusion-volume-independent early-to-late contrast concentration ratio ΔR1early/ΔR1late, where ΔR1 = 1/T1post-contrast - 1/T1native. RESULTS: Native T1 was lower in pericardial effusions (n = 69) than in pleural effusions (n = 54) (median [interquartile range], 2912 [2567-3152] vs 3148 [2692-3494] ms, p = 0.005). Pericardial and pleural effusions did not differ with regards to ΔR1early (0.05 [0.03-0.10] vs 0.07 [0.03-0.12] s- 1, p = 0.38). Compared to pleural effusions, pericardial effusions had a higher ΔR1late (0.8 [0.6-1.2] vs 0.4 [0.2-0.6] s- 1, p < 0.001) and ΔR1early/ΔR1late (0.19 [0.08-0.30] vs 0.12 [0.04-0.19], p < 0.001). CONCLUSIONS: T1 mapping shows that extracellular GBCA is excreted into pericardial and pleural effusions. Consequently, the previously used term vicarious excretion is misleading. Compared to pleural effusions, pericardial effusions had both a lower native T1, consistent with lesser relative fluid content in relation to other components such as proteins, and more prominent early excretion dynamics, which could be related to inflammation. The clinical diagnostic utility of T1 mapping to determine quantitative contrast dynamics in pericardial and pleural effusions merits further investigation.
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Medios de Contraste/farmacocinética , Cardiopatías/diagnóstico por imagen , Imagen por Resonancia Magnética , Meglumina/farmacocinética , Compuestos Organometálicos/farmacocinética , Derrame Pericárdico/diagnóstico por imagen , Derrame Pleural/diagnóstico por imagen , Anciano , Medios de Contraste/administración & dosificación , Femenino , Humanos , Masculino , Meglumina/administración & dosificación , Persona de Mediana Edad , Compuestos Organometálicos/administración & dosificación , Derrame Pericárdico/metabolismo , Derrame Pleural/metabolismo , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
Background Otherwise healthy women at high risk for breast cancer undergo annual contrast agent-enhanced breast MRI screening examinations, resulting in high cumulative doses of gadolinium-based contrast agents (GBCAs). Whereas the majority of studies showed no T1 signal ratio increase in deep brain nuclei after more than six doses of macrocyclic GBCA, this has not been explored in a healthy study population. Purpose To assess whether women who are administered large cumulative doses of macrocyclic GBCA with breast MRI at high-risk breast cancer screening exhibit T1 alterations in deep brain nuclei. Materials and Methods In this prospective study from November 2017 to March 2018, healthy women who were either exposed (because of high-risk breast cancer screening) or unexposed to only gadoterate meglumine underwent 3.0-T brain MRI with a dedicated head coil, including T1 mapping and magnetization-prepared rapid gradient-echo sequences. T1 times and T1 signal intensities were measured in the dentate nucleus (DN), globus pallidus (GP), crus anterior of capsula interna (CA), and pons. Ratios of DN to pons and GP to CA were calculated, and univariable Pearson correlation coefficients were calculated. Multivariable analysis included partial regression analysis. Results This study evaluated 25 women (mean age, 51 years ± 11 [standard deviation]) who were exposed to a mean GBCA dose of 129 mL (median 112 mL; range, 70-302 mL) and 16 women (mean age, 37 years ± 10) who were never exposed to any GBCA. Infratentorially, no correlation between cumulative GBCA dose and T1 times or signal intensity ratios was detected (P = .66 and .55, respectively). In partial correlation analysis by considering age as a confounder, there was a moderate negative correlation between GP-to-CA ratio and GBCA dose (r = -0.40; P = .01) but not for GP T1 times (r = 0.19; P = .24). Conclusion After administration of relatively large cumulative doses of gadoterate dimeglumine, healthy women at high risk for breast cancer who underwent annual contrast-enhanced breast MRI screening did not exhibit T1 signal increase in deep brain nuclei at 3.0-T MRI. © RSNA, 2019.
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Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Medios de Contraste/administración & dosificación , Imagen por Resonancia Magnética/métodos , Meglumina/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Adulto , Anciano , Medios de Contraste/farmacocinética , Femenino , Humanos , Meglumina/farmacocinética , Persona de Mediana Edad , Compuestos Organometálicos/farmacocinética , Estudios ProspectivosRESUMEN
OBJECTIVE: Recent studies reported a signal intensity increase in the deep cerebellar nuclei (DCN) on magnetic resonance images caused by gadolinium deposition after the injection of gadolinium-based contrast agents (GBCAs). There is an ongoing debate if the propensity of a GBCA to deposit gadolinium is primarily determined by its class as either linear or macrocyclic. In the current study, we aimed to compare the amount and the distribution of retained gadolinium of linear and macrocyclic GBCAs in the DCN after a single injection at a dose comparable to a human patient's in a large animal model. MATERIALS AND METHODS: Eighteen sheep were randomly assigned in 6 groups of 3 animals, which received a single injection of 0.1 mmol/kg body weight of either the macrocyclic GBCAs gadobutrol, gadoteridol, or gadoterate meglumine; the linear GBCAs gadobenate dimeglumine or gadodiamide; or saline. Animals were euthanized 10 weeks after injection. Local distribution and concentration of gadolinium and colocalization to other metals (iron, zinc, copper) in the DCN was assessed by laser ablation-inductively coupled plasma-mass spectrometry. RESULTS: Average gadolinium concentration for the macrocyclic GBCAs and the saline group was below the limit of quantification (5.7 ng/g tissue). In contrast, 14 (for gadobenate) and 27 (for gadodiamide) times more gadolinium than the limit of quantification was found for the linear GBCAs gadobenate (mean, 83 ng/g) or gadodiamide (mean, 155 ng/g brain tissue). Gadolinium distribution colocalized with other metals for linear GBCAs and a specific accumulation in the DCN was found. DISCUSSION: The current study supports the hypothesis that the amount of gadolinium deposited in the brain is primarily determined by its class as either macrocyclic or linear. The accumulation of gadolinium in the DCN for linear GBCAs explains the hyperintensities in the DCN found in previous patient studies with linear GBCAs.
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Encéfalo/metabolismo , Medios de Contraste/farmacocinética , Gadolinio/farmacocinética , Animales , Medios de Contraste/administración & dosificación , Femenino , Gadolinio/administración & dosificación , Gadolinio DTPA/administración & dosificación , Gadolinio DTPA/farmacocinética , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacocinética , Humanos , Meglumina/administración & dosificación , Meglumina/análogos & derivados , Meglumina/farmacocinética , Modelos Animales , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , OvinosRESUMEN
PURPOSE: To evaluate gadolinium (Gd) retention and clearance in the brain of diabetic rats after administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. MATERIALS AND METHODS: Both diabetic rats (n = 52) and normal rats (n = 52) intravenously received 20 injections of 0.6 mmol Gd/kg gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, or saline. Both diabetic rats and normal rats were divided into 2 subgroups of 24 and 28 rats for the 7-day and 42-day evaluations (i.e., they were sacrificed at 7 days (n = 6 per group) and 42 days (n = 7 per group)), respectively, after the last injection. For the 7-day subgroup, 6 rats were euthanized for inductively coupled plasma mass spectrometry (ICP-MS) analysis. For the 42-day subgroup, 6 rats underwent T1-weighted magnetic resonance imaging (MRI) and ICP-MS, and 1 rat was analyzed by transmission electron microscopy (TEM). RESULTS: The T1 enhancements in the deep cerebellar nuclei (DCNs) of diabetic rats were lower than those of normal rats in both linear Gd-based contrast agent (GBCA) groups (p < 0.05). The average Gd concentrations in the brains of diabetic rats were significantly lower than those of healthy rats in both the short-term groups and long-term groups (p < 0.05). The highest Gd retentions were in the olfactory bulb, DCN, and striatum with gadodiamide. Compared with the results obtained 7 days after the last injection, the residual Gd concentrations of the 42-day subgroups in the brains of diabetic rats showed no significant difference in both linear GBCA groups (p>0.05). CONCLUSIONS: Compared with normal rats, the diabetic status decreased the residual Gd concentrations in the brain after multiple administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. The clearable fraction of Gd in the brain was eliminated faster in diabetic rats than in normal rats.
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Encéfalo , Diabetes Mellitus Experimental , Gadolinio DTPA , Imagen por Resonancia Magnética , Meglumina , Compuestos Organometálicos , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Diabetes Mellitus Experimental/diagnóstico por imagen , Diabetes Mellitus Experimental/metabolismo , Gadolinio/farmacocinética , Gadolinio/farmacología , Gadolinio DTPA/farmacocinética , Gadolinio DTPA/farmacología , Masculino , Meglumina/farmacocinética , Meglumina/farmacología , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
PURPOSE: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. METHODS: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. RESULTS: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts. CONCLUSION: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models.
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Medios de Contraste/farmacocinética , Imagen por Resonancia Magnética/métodos , Animales , Medios de Contraste/administración & dosificación , Medios de Contraste/análisis , Heces/química , Gadolinio DTPA/administración & dosificación , Gadolinio DTPA/análisis , Gadolinio DTPA/farmacocinética , Humanos , Masculino , Meglumina/administración & dosificación , Meglumina/análogos & derivados , Meglumina/análisis , Meglumina/farmacocinética , Ratones , Ratones Transgénicos , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/análisis , Compuestos Organometálicos/farmacocinética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
PURPOSE: To quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used. METHODS: A total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed. RESULTS: Seven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001). CONCLUSION: Gadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.