Gadopentetic Acid (Gd-DTPA): A Comprehensive Pharmacological, Clinical, and Safety Review of a First-Generation MRI Contrast Agent

I. Introduction: The Advent of Paramagnetic Contrast in Magnetic Resonance Imaging

Historical Context: The Need for Contrast Enhancement in Early MRI

Magnetic Resonance Imaging (MRI) emerged as a revolutionary medical imaging modality by providing unparalleled soft tissue detail without the use of ionizing radiation. The fundamental principle of MRI relies on detecting signals from hydrogen protons within the body's water molecules after they are manipulated by strong magnetic fields and radiofrequency pulses.[1] The resulting image contrast is derived from intrinsic tissue properties, primarily the proton density and the relaxation time constants known as T1 (longitudinal or spin-lattice relaxation) and T2 (transverse or spin-spin relaxation).[4] However, in the early stages of its clinical application, a significant limitation became apparent: the inherent differences in these properties between various tissues, particularly between healthy and pathological tissues, were often subtle. This frequently resulted in insufficient contrast to confidently delineate, characterize, and diagnose disease.[4] This challenge created a clear and pressing need for exogenous pharmaceutical agents that could selectively alter the relaxation properties of tissues, thereby increasing the informational content of the diagnostic images and improving both the sensitivity and specificity of the examination.[2]

Gadopentetic Acid: The First-in-Class Gadolinium-Based Contrast Agent (GBCA)

The development of gadopentetic acid represented a landmark achievement that addressed this critical need and fundamentally transformed the field of diagnostic radiology. Described in 1981 by Hanns-Joachim Weinmann and colleagues and subsequently introduced for clinical use in 1987 by Schering AG under the brand name Magnevist®, gadopentetic acid was the first-ever MRI contrast agent to receive regulatory approval.[6] Its introduction marked a paradigm shift, enabling what is now known as contrast-enhanced MRI (CE-MRI).[1] The conceptual breakthrough behind gadopentetic acid was the harnessing of the potent paramagnetic properties of the gadolinium ion (

Gd3+), a rare earth metal from the Lanthanide series.[2] With seven unpaired electrons, the

Gd3+ ion possesses one of the largest magnetic moments of any stable ion, making it exceptionally effective at influencing the relaxation rates of nearby water protons.[4]

The Chelation Principle

The clinical use of gadolinium presented a formidable challenge: the free, uncomplexed Gd3+ ion is highly toxic to biological systems, in part because its ionic radius is similar to that of calcium (Ca2+), allowing it to compete with and disrupt essential calcium-dependent cellular processes.[2] The solution to this problem, and the core of gadopentetic acid's design, was the principle of chelation. The toxic

Gd3+ ion was tightly bound within a molecular cage formed by a multidentate organic ligand, diethylenetriaminepentaacetic acid (DTPA), also known as pentetic acid.[1] The resulting complex, gadopentetic acid, was designed to be a stable, water-soluble entity that could be administered intravenously, exert its paramagnetic effect, and then be rapidly excreted from the body before any significant release of the toxic free gadolinium could occur.[2]

Thesis Overview: A Critical Examination of a Dual Legacy

This report provides a comprehensive and critical examination of the dual legacy of gadopentetic acid. It is presented, on one hand, as a revolutionary diagnostic tool that unlocked the full potential of MRI, enabling the visualization of pathologies with unprecedented clarity and becoming an indispensable agent in neuroradiology and beyond.[11] On the other hand, it serves as a profound cautionary tale in pharmacovigilance. Decades of post-marketing surveillance have uncovered severe, late-discovered toxicities—most notably Nephrogenic Systemic Fibrosis (NSF) and the phenomenon of gadolinium retention—that have fundamentally altered its risk-benefit profile.[3] The very design of the molecule, a linear chelate structure once thought to be sufficiently stable, was ultimately revealed to be its greatest liability. Under certain physiological conditions, such as impaired renal function, the chelate's stability proved inadequate, leading to the dissociation of the complex and the in vivo release of the toxic

Gd3+ ion it was designed to contain.[8] This dissociation is the direct etiological cause of NSF, a devastating disease the chelation was intended to prevent. This central paradox—where the agent's primary safety feature contained a latent flaw that became the source of its most severe toxicity—has led to major regulatory actions, including market suspension in some regions, and has permanently reshaped the landscape of contrast media safety and development.[15]

II. Physicochemical Properties, Synthesis, and Formulation

A. Chemical Identity and Structure

A precise understanding of the chemistry of gadopentetic acid requires differentiating between the active pharmaceutical moiety and the formulated drug product.

Gadopentetic Acid (The Active Moiety)

Gadopentetic acid is the core complex formed between a single gadolinium(III) ion (Gd3+) and the chelating ligand pentetic acid (diethylenetriaminepentaacetic acid, DTPA).[1]

• Chemical Formula: The empirical formula for the complex is C14​H20​GdN3​O10​.[1]
• Molecular Weight: The average molecular weight is consistently reported as 547.57 g/mol or 547.58 g/mol, with a monoisotopic mass of 548.03898 Da.[1]
• CAS Number: The Chemical Abstracts Service (CAS) registry number for gadopentetic acid is 80529-93-7.[13]
• IUPAC Name: The systematic IUPAC name for the chelating portion of the molecule is 2-[bis[carboxylatomethyl(carboxymethyl)amino]ethyl]amino]acetate.[16] The Chemical Abstracts Index Name for the complex is Gadolinate(2–), [N,N-bis[bis[(carboxy-κO)methyl]amino-κN]ethyl]glycinato(5–)-κN,κO]-, hydrogen (1:2).[13]
• Structure: In the complex, the Gd3+ ion is 9-coordinate. It is bound by eight donor atoms from the DTPA ligand: three nitrogen atoms and five oxygen atoms from the deprotonated carboxylate groups. Crucially, the ninth coordination site is occupied by a labile water molecule (H2​O). This inner-sphere water molecule is not merely structural; it is essential to the agent's mechanism of action, as its rapid exchange with surrounding water molecules is a primary pathway for propagating the paramagnetic effect.[6]

Gadopentetate Dimeglumine (The Pharmaceutical Salt)

For clinical use, gadopentetic acid is formulated as a highly water-soluble salt. This is achieved by combining the gadopentetic acid complex, which has a net charge of -2, with two molecules of the protonated amino sugar meglumine (N-methyl-D-glucamine) as counter-ions.[2] This formulated product is known as gadopentetate dimeglumine and is marketed under the brand name Magnevist®.[1]

• Chemical Formula: The formula for the dimeglumine salt is C28​H54​GdN5​O20​.[5]
• Molecular Weight: The molecular weight of the complete salt is 938.0 g/mol.[5]
• CAS Number: The CAS number for gadopentetate dimeglumine is 86050-77-3.[22]

B. Physicochemical Characteristics

• Appearance: In its solid, purified form, gadopentetic acid is a white powder.[13] The final pharmaceutical product, Magnevist® injection, is a sterile, clear, colorless to slightly yellow aqueous solution.[5]
• Solubility: The addition of meglumine significantly enhances water solubility. While the acid form is only slightly soluble in water, the dimeglumine salt is freely soluble.[17] A water solubility of 100 g/L has been reported for the complex.[13]
• Physical Properties of the Injection: The standard Magnevist® injection is a 0.5 mol/L solution. It is markedly hypertonic, with a measured osmolality of 1,960 mOsmol/kg, which is approximately 6.9 times the osmolality of human plasma.[5] The pH of the injectable solution is maintained in a range of 6.5 to 8.0.[25]

C. Chemical Synthesis and Industrial Preparation

The industrial synthesis of high-purity gadopentetate dimeglumine involves a multi-step process designed to ensure stability and minimize impurities.

• Core Reaction: The fundamental step is the complexation reaction. Gadolinium oxide (Gd2​O3​) is mixed and dissolved with pentetic acid (DTPA) in purified water. The mixture is then heated, for example to 90–96 °C, and stirred for several hours until the reaction is complete and the solution clarifies, yielding an aqueous solution of gadolinium-DTPA (gadopentetic acid).[27]
• Formulation: In a subsequent step, a separate aqueous solution of meglumine is prepared and added to the gadopentetic acid solution to form the final gadopentetate dimeglumine salt.[27]
• Purification: Early production methods were noted to lack robust purification steps, leading to lower purity products with residual impurities from raw materials or side reactions. Modern patented processes emphasize the importance of purification to improve product quality and safety. This can involve steps such as passing the solution through a resin column, which can increase the final purity to over 99.5% and, after crystallization, to as high as 99.9%.[27]
• Novel Synthesis Methods: Beyond conventional thermal heating, researchers have explored more efficient and environmentally friendly synthesis routes. One such approach utilizes ultrasound energy, which, through acoustic cavitation, dramatically reduces reaction times from many hours to as little as 20-30 minutes while providing high yields and purity. This method can circumvent the need for extensive recrystallization steps.[29] Other patented innovations focus on producing stable, filterable solid powder forms of gadolinium chelates for easier handling and formulation [30] or creating novel conjugates by bonding Gd-DTPA to other molecules, such as graphene oxide, to develop new agents with different properties and potential applications.[31]

The following table consolidates the key identifying and physical properties of both the active moiety and the formulated drug product.

Property	Gadopentetic Acid	Gadopentetate Dimeglumine	Source(s)
DrugBank ID	DB00789	DBSALT002762	1
Modality	Small Molecule	Salt of Small Molecule	1
Brand Name	-	Magnevist®	1
CAS Number	80529-93-7	86050-77-3	20
Chemical Formula	C14​H20​GdN3​O10​	C28​H54​GdN5​O20​	1
Average Mol. Wt. (g/mol)	547.58	938.0	1
Appearance	White Powder (solid)	White Powder (solid)	13
Water Solubility	Slightly Soluble	Freely Soluble	17
pH (of injection)	N/A	6.5 - 8.0	25
Osmolality (of injection)	N/A	1,960 mOsmol/kg	5

III. Pharmacology and Mechanism of Action

A. Principles of Paramagnetism and Proton Relaxation in MRI

The diagnostic utility of gadopentetic acid is rooted in the fundamental physics of MRI and the unique properties of the gadolinium ion. MRI generates images by measuring the radiofrequency signals emitted from hydrogen protons in water molecules as they relax back to an equilibrium state after being perturbed within a powerful magnetic field.[1] The contrast between different tissues in the resulting image is determined by local differences in proton density and, more importantly, by the rates at which these protons relax. These rates are quantified by two time constants: T1 (spin-lattice relaxation), which describes the time taken for protons to realign with the main magnetic field, and T2 (spin-spin relaxation), which describes the time over which protons lose phase coherence with each other.[3]

Gadopentetic acid functions as a paramagnetic contrast agent.[1] This property is conferred by the gadolinium(III) ion (

Gd3+) at its core. Gd3+ has a 4f⁷ electronic configuration, resulting in seven unpaired electrons.[4] This large number of unpaired electrons endows the ion with a strong magnetic moment. When introduced into the strong external magnetic field of an MRI scanner, the

Gd3+ ion develops a large induced magnetic moment, which in turn creates a powerful, fluctuating local magnetic field in its immediate vicinity.[2]

B. Molecular Mechanism of Contrast Enhancement

The primary mechanism of action of gadopentetic acid is the acceleration of the relaxation rates—or shortening of the relaxation times—of nearby water protons.[1] The fluctuating local magnetic field generated by the

Gd3+ ion provides a highly efficient pathway for energy exchange with surrounding protons. This allows the protons to dissipate their energy and return to their low-energy equilibrium state much more rapidly, thereby shortening their T1 relaxation time.[2] To a lesser extent, it also enhances dephasing, which shortens the T2 relaxation time.

At the typical doses used in clinical practice, the dominant effect is on T1 relaxation.[2] On T1-weighted imaging sequences, which are designed to be sensitive to differences in T1 times, tissues with shorter T1 values produce a stronger signal and appear brighter. Therefore, when gadopentetic acid accumulates in a particular tissue, it dramatically shortens the T1 of the water in that tissue, leading to a significant increase in signal intensity. This "T1 enhancement" makes the tissue appear bright on the T1-weighted image, improving its visibility and contrast relative to surrounding, unenhanced tissues.[2]

A critical feature contributing to the efficacy of the Gd-DTPA complex is the single, labile water molecule directly coordinated to the central Gd3+ ion.[6] This "inner-sphere" water molecule is in rapid exchange with the vast pool of "bulk" water molecules in the surrounding tissue. This rapid exchange process acts as a highly efficient shuttle, continuously bringing new water molecules into the immediate, powerful influence of the paramagnetic center and then releasing them back into the bulk environment. This mechanism effectively transfers the potent relaxing effect of a single gadolinium ion to a very large number of water protons, significantly amplifying the agent's overall contrast-enhancing power, or "relaxivity".[6]

C. The Critical Role of Chelate Structure: Linear vs. Macrocyclic Agents

The chemical structure of the chelating ligand is not merely an academic detail; it is the single most important determinant of a GBCA's long-term safety. GBCAs are broadly classified based on the architecture of their chelating ligand. Gadopentetic acid (Gd-DTPA) is the archetypal ionic, linear GBCA.[6] Its DTPA ligand is a flexible, open-chain molecule that wraps around the

Gd3+ ion to coordinate it.[32]

This linear structure stands in stark contrast to that of macrocyclic agents, such as gadoterate meglumine (Gd-DOTA). In these agents, the ligand forms a rigid, pre-organized molecular cage or cavity that encapsulates the Gd3+ ion.[4] This structural difference has profound implications for the stability of the complex. Macrocyclic agents exhibit significantly higher thermodynamic stability and, more importantly, kinetic inertness. This means they are far less likely to release the toxic free

Gd3+ ion through dissociation or transmetallation (displacement by endogenous ions like zinc) while in the body.[32]

The lower kinetic stability of linear agents like gadopentetic acid is the direct cause of their higher risk of causing NSF and their tendency to result in greater long-term gadolinium retention in tissues compared to the safer macrocyclic agents.[3] This fundamental link between molecular structure and clinical risk profile is central to understanding the evolution of GBCA safety standards and the current preference for macrocyclic agents in clinical practice. The following table provides a comparative classification of gadopentetic acid alongside other representative GBCAs, illustrating this critical relationship.

Agent Name	Brand Name(s)	Structural Class	Ionicity	NSF Risk Group (ACR/EMA)	Gadolinium Retention Profile	Source(s)
Gadopentetic acid	Magnevist	Linear	Ionic	High (Group 1)	Moderate / High	6
Gadodiamide	Omniscan	Linear	Non-ionic	High (Group 1)	High	8
Gadoversetamide	OptiMARK	Linear	Non-ionic	High (Group 1)	High	8
Gadoterate meglumine	Dotarem, Clariscan	Macrocyclic	Ionic	Low (Group 2)	Low	8
Gadobutrol	Gadavist, Gadovist	Macrocyclic	Non-ionic	Low (Group 2)	Low	8
Gadoteridol	ProHance	Macrocyclic	Non-ionic	Low (Group 2)	Low	8

IV. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

A. Administration and Distribution

Gadopentetic acid is formulated for and administered exclusively by intravenous injection, typically given as a rapid bolus.[20] Following injection, the complex is hydrophilic and rapidly distributes from the plasma into the extracellular fluid space throughout the body.[1] Studies in healthy subjects have determined its volume of distribution to be approximately 266 ± 43 mL/kg.[16] The initial distribution phase is very quick, characterized by a distribution half-life of about 12 minutes.[1] It is important to note that the agent is poorly absorbed when taken orally, a fact that mitigates the risk of systemic exposure to breastfed infants whose mothers have received the contrast agent.[16]

B. The Blood-Brain Barrier (BBB) and CNS Distribution

The pharmacokinetic behavior of gadopentetic acid with respect to the central nervous system is the cornerstone of its utility in neuro-imaging. The Gd-DTPA complex is a hydrophilic molecule and, as such, does not cross the intact blood-brain barrier (BBB).[1] Consequently, in a healthy state, it does not accumulate in normal brain parenchyma. It also does not enhance CNS lesions that have not caused a disruption of the BBB, such as simple cysts or mature post-operative scars.[1]

However, in the presence of many pathologies—including neoplasms, abscesses, and subacute infarcts—the integrity of the BBB is compromised, or the lesion exhibits abnormal vascularity.[1] This disruption allows the gadopentetic acid complex to leak from the intravascular compartment into the interstitial space of the lesion. This localized accumulation leads to strong T1 shortening and brilliant enhancement on T1-weighted images, making the pathology highly conspicuous against the unenhanced background of normal brain tissue.[2]

C. Metabolism

Gadopentetic acid is designed to be biologically inert. There is no evidence of any biotransformation or decomposition of the complex in the body.[16] It is excreted from the body completely unchanged, underscoring its role as a passive diagnostic tracer rather than a metabolically active drug.[2]

D. Excretion

The elimination of gadopentetic acid from the body is almost exclusively a renal process.[1] The complex undergoes efficient clearance from the bloodstream via glomerular filtration in the kidneys. The near-identical values for renal clearance (1.76 ± 0.39 mL/min/kg) and total plasma clearance (1.94 ± 0.28 mL/min/kg) provide strong evidence that the kidneys are the sole significant route of elimination and that the drug's pharmacokinetic properties are not altered during its passage through the renal system.[5]

In individuals with normal renal function, this elimination process is rapid and efficient. Approximately 83% of an administered dose is excreted in the urine within 6 hours, with 91% cleared by 24 hours post-injection.[1] The elimination half-life in this population is approximately 90 to 100 minutes.[1]

E. Pharmacokinetics in Special Populations: Renal Impairment

The pharmacokinetic profile of gadopentetic acid is drastically altered in patients with renal impairment, a variation that has profound and severe clinical consequences. As renal function declines, the ability of the kidneys to filter and excrete the drug is diminished, leading to a dramatic prolongation of its elimination half-life. In patients with mild to moderate renal impairment, the half-life increases to 3 to 4 hours.[37] In patients with severe renal disease or end-stage renal disease (ESRD), the half-life can be extended to as long as 30 hours or more.[8]

This massively increased residence time of the drug in the body is the critical factor that precipitates its most feared toxicity. The prolonged exposure of the relatively unstable linear Gd-DTPA complex to the physiological environment increases the probability of its dissociation. This allows the toxic free Gd3+ ion to be released from its chelate, where it can then deposit in tissues and trigger the pathological cascade of Nephrogenic Systemic Fibrosis (NSF).[8] The direct, quantitative relationship between declining renal function, prolonged drug elimination, and the risk of catastrophic toxicity is the central pharmacokinetic principle underpinning all safety warnings and contraindications for this agent. The following table starkly illustrates this relationship.

Parameter	Value in Healthy Subjects	Value in Mild/Moderate Renal Impairment	Value in Severe Renal Impairment / ESRD	Source(s)
Elimination Half-life (t1/2​)	~100 minutes	3 - 4 hours	>30 hours	1
Distribution Half-life (t1/2​)	~12 minutes	Not specified	Not specified	1
Volume of Distribution (Vd​)	~266 mL/kg	Not specified	Not specified	16
Plasma Clearance	~1.94 mL/min/kg	Decreased	Severely Decreased	16
Primary Route of Elimination	Renal (Glomerular Filtration)	Renal (Glomerular Filtration)	Renal (Glomerular Filtration)	4

V. Clinical Indications and Diagnostic Utility

A. FDA-Approved Indications

Gadopentetic acid is classified as a diagnostic aid, specifically as a paramagnetic contrast agent for use in magnetic resonance imaging.[1] According to its FDA labeling, it is approved for intravenous use in adults and pediatric patients aged 2 years and older to improve the visualization of various tissues and pathologies.[1] The specific approved indications include:

• Central Nervous System (CNS): For use with MRI to visualize lesions with abnormal vascularity within the brain (intracranial lesions), the spine, and their associated tissues. This has been shown to facilitate the visualization of pathologies including, but not limited to, tumors, abscesses, and subacute infarcts.[1]
• Extracranial/Extraspinal Tissues: To facilitate the visualization of lesions with abnormal vascularity in the head and neck regions.[1]
• Body Imaging: To facilitate the visualization of lesions with abnormal vascularity in the body, with the specific exclusion of cardiac imaging.[1]

B. Diagnostic Efficacy and Application

The fundamental role of gadopentetic acid is to enhance the contrast in MRI images, thereby providing more detailed and lucid information to support diagnosis and evaluation.[12] It achieves this by accumulating in areas of abnormal vascularity or disruption of normal physiological barriers, such as the blood-brain barrier.[2] This accumulation increases the local signal intensity on T1-weighted images, which improves the differentiation between pathological and normal tissues and helps to delineate the extent and nature of disease.[2]

A common application is in Dynamic Contrast-Enhanced MRI (DCE-MRI). In this technique, the agent is administered as a rapid intravenous bolus, and a series of fast images are acquired over time to track the agent's passage through the tissue. This allows for the quantitative assessment of physiological parameters like tissue perfusion, blood volume, and vascular permeability, which are valuable in oncology for characterizing tumors and assessing treatment response.[20]

C. Specialized Applications: dGEMRIC

Beyond its general use, gadopentetic acid possesses a unique property that enables a specialized musculoskeletal imaging technique known as delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC).[6] This application stems directly from the fact that the Gd-DTPA complex is ionic, carrying a net charge of -2 (

2−). Articular cartilage, the tissue lining the surfaces of joints, is rich in proteoglycan aggregates, which contain negatively charged glycosaminoglycan (GAG) side chains. Due to electrostatic repulsion, the negatively charged gadopentetate ions distribute within the cartilage in a manner that is inversely proportional to the local concentration of these negatively charged GAGs.

In healthy cartilage with a high GAG concentration, the contrast agent is repelled and its concentration remains low. In damaged cartilage, such as in early osteoarthritis, the GAG content is depleted. This reduction in negative charge allows for a higher concentration of the gadopentetate agent to diffuse into the cartilage matrix. By measuring the T1 relaxation time of the cartilage after allowing the contrast agent to reach equilibrium (the "delayed" aspect), clinicians can create a quantitative map of GAG concentration. This provides a non-invasive biochemical index of cartilage health, allowing for the detection of early degenerative changes before structural damage becomes visible on standard MRI.[6]

This specific application creates a notable clinical dilemma. The very property that enables this valuable diagnostic technique—the ionic charge of the linear chelate—is also intrinsically linked to the physicochemical characteristics that contribute to its lower stability and higher overall safety risk compared to newer, non-ionic or macrocyclic agents. This creates a complex risk-benefit calculation where a generally higher-risk agent may be the preferred or even the only tool available for answering a specific and important clinical question in musculoskeletal imaging. It highlights that risk-benefit assessments must be nuanced and tailored to the specific diagnostic task, rather than being applied as a universal rule.

VI. Dosage, Administration, and Handling

A. Dosing Regimens

• Standard Recommended Dose: For all approved indications in both adults and pediatric patients (2 years of age and older), the standard recommended dose is 0.1 mmol per kilogram (mmol/kg) of body weight. This corresponds to an injection volume of 0.2 milliliters per kilogram (mL/kg) of the standard 0.5 mmol/mL Magnevist® solution.[36]
• Maximum Doses and Precautions: While some clinical guidelines mention the possibility of using higher or repeated doses in specific circumstances—such as a second injection of 0.1 mmol/kg (or up to 0.2 mmol/kg in adults) to improve diagnostic confidence, or a total dose of 0.3 mmol/kg (0.6 mL/kg) for tumor exclusion or angiography in adults—this practice is now strongly discouraged.[39] Regulatory warnings from the FDA explicitly advise against exceeding the recommended dose. This is because higher than recommended or repeated doses are recognized as factors that increase the risk for developing both Nephrogenic Systemic Fibrosis (NSF) and long-term gadolinium retention.[5] A sufficient period of time must be allowed for the drug to be eliminated from the body before any re-administration.[37]
• Weight Limitation: It is noted in the prescribing information that dosing for patients weighing in excess of 286 pounds (approximately 130 kg) has not been specifically studied.[36]

B. Administration

• Method of Injection: Gadopentetate dimeglumine is administered as a rapid bolus intravenous injection. To ensure patient safety and comfort, the injection rate should not exceed 10 mL per 15 seconds.[36]
• Saline Flush: To ensure the complete and accurate delivery of the full dose of the contrast medium from the syringe and tubing into the patient's circulation, the injection should be immediately followed by a 5 mL flush with a sterile saline solution (0.9% sodium chloride).[36]
• Patient Monitoring: As a general precaution for intravenous contrast media, it is recommended that the injection be administered with the patient in a recumbent position. The patient should be kept under clinical supervision following the administration, as the majority of acute adverse reactions occur within the first 30 minutes.[39]

C. Pharmaceutical Formulation and Handling

• Product Formulation: Magnevist® is supplied as a sterile, 0.5 mmol/mL aqueous solution of gadopentetate dimeglumine. This corresponds to a concentration of 469.01 mg of gadopentetate dimeglumine per mL. It is available in various presentations, including single-dose vials and pre-filled syringes.[5]
• Aseptic Handling: The solution should be drawn into the syringe immediately prior to administration. It contains no antimicrobial preservative, making strict aseptic technique essential to prevent contamination.[5] The rubber stopper on a vial should be pierced only once.
• Visual Inspection and Disposal: Before use, the solution should be visually inspected. It should not be used if it is discolored, if particulate matter is present, or if the container appears to be damaged. In accordance with regulations for pharmaceutical waste, any unused portion of the contrast medium in a vial or syringe must be discarded after a single use.[39]

VII. The Critical Safety Profile, Part 1: Nephrogenic Systemic Fibrosis (NSF)

A. The Discovery and Pathophysiology of NSF

Nephrogenic Systemic Fibrosis (NSF), first identified in the late 1990s and linked to gadolinium-based contrast agents (GBCAs) in 2006, is a rare, progressive, and profoundly debilitating systemic disorder.[8] In its most severe form, it can be fatal.[5] The disease is characterized by the widespread formation of fibrous connective tissue, primarily affecting the skin, which becomes thickened, coarse, hard, and sometimes bound down, leading to painful joint contractures and severe loss of mobility.[8] The fibrosis is not limited to the skin; it can also involve internal organs, including the lungs, heart, liver, and skeletal muscles, leading to multi-organ failure.[8]

The etiology of NSF is iatrogenic, caused exclusively by exposure to GBCAs in a specific patient population: those with significantly impaired renal function.[8] The prevailing pathophysiological theory holds that in these patients, the dramatically prolonged elimination half-life of the GBCA provides the necessary time for the gadolinium complex to dissociate.[8] For less stable, linear agents like gadopentetic acid, this allows the toxic, free gadolinium ion (

Gd3+) to be released from its protective chelate. This free Gd3+ is then believed to form insoluble precipitates, such as gadolinium phosphate, which deposit in tissues.[8] These deposits are thought to act as a potent trigger, activating a massive and uncontrolled inflammatory and fibrotic response driven by circulating fibrocytes, tissue macrophages, and fibroblasts, culminating in the extensive tissue remodeling characteristic of NSF.[8]

B. The FDA Black Box Warning and Regulatory Actions

In response to the growing number of NSF cases linked to GBCAs, the U.S. Food and Drug Administration (FDA) took significant regulatory action. In 2007, the agency mandated the addition of a Boxed Warning—its most serious safety alert—to the labeling of all GBCAs.[38] This warning for gadopentetic acid (Magnevist®) was updated and strengthened in 2010.[5]

The core message of the Boxed Warning is unequivocal: GBCAs increase the risk for NSF among patients with impaired drug elimination. It explicitly states that the use of these agents should be avoided in high-risk patients unless the diagnostic information is deemed essential and cannot be obtained with non-contrasted MRI or other imaging modalities.[5] Taking a different approach to risk mitigation, the European Medicines Agency (EMA) went further. In 2017, its Pharmacovigilance Risk Assessment Committee recommended the suspension of the marketing authorization for all intravenous linear GBCAs, including gadopentetic acid, citing the unacceptable risk of NSF and gadolinium retention in the brain, particularly given the availability of safer macrocyclic alternatives.[15]

C. Risk Stratification and High-Risk Groups

The risk of developing NSF is not uniform across all patients or all GBCAs. It is highly stratified based on the patient's renal function.

• Highest Risk and Contraindication: The risk for NSF is highest in patients with chronic, severe kidney disease, defined as a glomerular filtration rate (GFR) of less than 30 mL/min/1.73m², and in patients with acute kidney injury (AKI) of any severity.[5] In these patient populations, the use of gadopentetic acid is contraindicated.[37]
• Moderate Risk: The risk is considered lower, but still present, for patients with chronic, moderate kidney disease (GFR 30–59 mL/min/1.73m²).[5]
• Low to No Risk: The risk is considered little, if any, for patients with chronic, mild kidney disease (GFR 60–89 mL/min/1.73m²) and is not reported in patients with normal renal function.[5]
• Other Risk Factors: Additional factors that increase the risk include the administration of higher-than-recommended doses or repeated doses of a GBCA.[38] Neonates up to 4 weeks of age are also considered a high-risk group due to their immature renal function, leading to a contraindication in some jurisdictions.[15]

D. The Role of Chelate Stability

The risk of NSF is also highly dependent on the specific GBCA used. Regulatory bodies and professional societies, such as the American College of Radiology (ACR), have classified GBCAs into risk groups based on their chemical structure and propensity to cause NSF. Gadopentetic acid (Magnevist®) is consistently placed in the highest-risk group (Group 1), alongside other linear agents such as gadodiamide (Omniscan) and gadoversetamide (OptiMARK).[8] This high-risk classification is a direct consequence of its

linear chemical structure, which, as previously discussed, is thermodynamically and kinetically less stable and therefore more prone to releasing free Gd3+ in vivo compared to the more stable, cage-like macrocyclic agents that constitute the low-risk group.[3]

VIII. The Critical Safety Profile, Part 2: Gadolinium Retention and Deposition

A. The Phenomenon of Gadolinium Retention

A second major safety concern, distinct from but related to NSF, emerged around 2013 with the discovery of long-term gadolinium retention. Studies demonstrated that trace amounts of gadolinium can be retained in the body for months or even years following the administration of GBCAs, critically, even in patients with normal renal function.[3]

• Sites of Deposition: This retained gadolinium is not uniformly distributed. The highest concentrations have been consistently identified in bone, which appears to act as a long-term reservoir. Significant deposition also occurs in other organs, including the brain (with a predilection for the globus pallidus and dentate nucleus), skin, kidney, liver, and spleen.[32]
• Radiological Evidence: The deposition of gadolinium in the brain is not just a microscopic finding; it can be visualized on subsequent MRI scans. Patients who have received multiple doses of certain GBCAs may demonstrate a progressive increase in signal intensity on unenhanced T1-weighted images in the globus pallidus and dentate nucleus.[32] This radiological finding has been directly correlated with the physical presence of gadolinium deposits in these structures in postmortem human and animal studies, confirming that the signal change is a true marker of metal deposition.[9]

B. Mechanism and Risk Factors for Retention

The primary factor determining the extent of gadolinium retention is the stability of the GBCA chelate.

• Chelate Stability is Key: The phenomenon is directly linked to the chemical structure of the agent. Linear GBCAs result in significantly more gadolinium retention than macrocyclic GBCAs.[32] Gadopentetic acid (Magnevist), as a linear ionic agent, is classified as having a "moderate" or "moderate-to-high" retention profile, substantially higher than any of the macrocyclic agents.[32]
• Mechanism of Deposition: The retained gadolinium is believed to exist in different chemical forms. Some may be intact chelate that is very slowly cleared from certain tissue compartments. More concerning is the portion that represents dissociated, de-chelated Gd3+. This free ion can form insoluble gadolinium phosphate or carbonate deposits or bind tenaciously to endogenous macromolecules, leading to very long-term retention.[8]
• At-Risk Populations: While retention appears to occur in all exposed individuals, certain populations may be at higher risk for potential clinical consequences. These include patients requiring multiple lifetime doses (e.g., those with multiple sclerosis or cancer undergoing surveillance), pregnant women and their fetuses, and pediatric patients, whose developing brains may be more vulnerable.[35]

C. The Unresolved Clinical Significance

The discovery of gadolinium deposition in the brain of patients with normal kidney function has raised significant safety concerns, but the clinical consequences, if any, remain a subject of intense debate and research.

• Official Regulatory Stance: As of its most recent reviews, the FDA has stated that it has not identified any adverse health effects from gadolinium retained in the brain of patients with normal renal function.[35] The agency has acknowledged the knowledge gaps and the theoretical risks, leading it to issue new class-wide warnings and require manufacturers to conduct further human and animal studies to assess the safety of all GBCAs.[34]
• Gadolinium Deposition Disease (GDD): A patient-reported syndrome, termed "Gadolinium Deposition Disease" or GDD, has been proposed to describe a constellation of symptoms that appear hours to months after GBCA exposure in patients with normal renal function. Reported symptoms are broad and include persistent headache, bone and joint pain, clouded mentation or "brain fog," and peripheral neuropathic pain in a "glove and stocking" distribution.[35] GDD is currently a proposed, not a proven, clinical entity. Its causal link to gadolinium retention is controversial and has not been established by mainstream medical and scientific bodies, though it remains an active area of research and litigation.[9]
• Potential for Other Toxicities: Preclinical research has raised other theoretical concerns. In vitro studies have demonstrated that gadolinium can be neurotoxic.[3] Furthermore, one recent study found that long-term treatment with gadopentetic acid could increase the expression of the TRPC5 ion channel in breast cancer cells, which was associated with increased resistance to chemotherapy. This raises the hypothesis that gadolinium deposition could, in some contexts, promote chemoresistance, although this has not been demonstrated clinically.[44]

The issue of gadolinium retention represents a paradigm shift in pharmacovigilance. The NSF crisis was a reaction to a clear and devastating clinical outcome. In contrast, the regulatory actions surrounding retention have been driven by evidence of tissue deposition alone, even in the absence of a definitively proven clinical disease in the renally normal population. This reflects a move toward the precautionary principle, where the permanent deposition of a potentially toxic heavy metal in the brain is considered by many to be an unacceptable risk, regardless of whether downstream harm has been proven. This shifts the burden of proof, compelling manufacturers not just to demonstrate acute safety, but to prove long-term biocompatibility and harmlessness—a much higher standard for all future medical implants and diagnostic agents.

IX. General Adverse Reactions, Contraindications, and Drug Interactions

A. Contraindications

Based on the well-established risk of NSF, the use of gadopentetate dimeglumine is absolutely contraindicated in several patient populations:

• Patients with a known history of a severe hypersensitivity reaction to gadopentetate dimeglumine or any of its components.[7]
• Patients with chronic, severe kidney disease, defined by a glomerular filtration rate (GFR) less than 30 mL/min/1.73m².[7]
• Patients with acute kidney injury (AKI).[7]
• In some jurisdictions, such as Canada and the EU, use is also contraindicated in neonates up to 4 weeks of age due to their immature renal function.[15]

B. General Adverse Reactions

Beyond the major risks of NSF and gadolinium retention, gadopentetic acid is associated with a range of other potential adverse effects.

• Common (Incidence ≥1%): The most frequently reported adverse reactions are typically mild and self-limiting. These include headache, nausea, and various injection site reactions such as pain, a sensation of coldness, or a feeling of warmth.[40] Dizziness is also reported as a common side effect.[40]
• Less Common/Rare but Serious Reactions:
• Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions, while rare, can occur and may be life-threatening. These reactions can involve cardiovascular (e.g., hypotension, shock), respiratory (e.g., bronchospasm, laryngeal edema), and/or cutaneous (e.g., urticaria, angioedema) manifestations. The risk is known to be higher in patients with a prior history of allergic reactions to other contrast media, as well as in patients with a history of bronchial asthma or other allergic disorders.[37] Symptoms requiring immediate medical attention include hives, difficulty breathing, and swelling of the face, tongue, or throat.[47]
• Cardiovascular: Serious cardiovascular events have been reported, including cardiac arrest, arrhythmia (bradycardia, tachycardia), transient changes in blood pressure, and thrombophlebitis.[37]
• Renal: In patients with pre-existing renal impairment, cases of acute renal failure or a significant worsening of renal function have been observed, typically occurring within 48 hours of injection. The risk is higher with increasing doses of the contrast agent.[11]
• Neurological: Seizures have been reported, particularly in patients with a known history of epilepsy. Other rare but serious neurological events include coma and speech disorders.[11]
• Injection Site Reactions: While mild discomfort is common, extravasation (leakage of the agent into the surrounding soft tissue) can cause more significant local irritation. In rare instances, severe tissue reactions including skin necrosis, fasciitis, and compartment syndrome requiring surgical intervention have occurred.[42]

C. Drug-Drug Interactions

The potential for drug-drug interactions with gadopentetic acid is primarily pharmacokinetic in nature, relating to its exclusive renal excretion.

• Mechanism: Most documented interactions involve competition for renal excretion pathways. As gadopentetic acid is cleared by the kidneys, co-administration with other drugs that are also renally excreted can affect the clearance of one or both agents.[1]
• Interactions:
• Drugs whose excretion may be decreased by Gadopentetic Acid: Gadopentetic acid may compete with and decrease the excretion rate of various other drugs, potentially leading to higher serum levels and an increased risk of their respective toxicities. A wide range of drugs fall into this category, including the antiviral abacavir, the bronchodilator salbutamol (albuterol), the anticoagulant warfarin, and certain antihemophilic factors.[1]
• Drugs that may decrease the excretion of Gadopentetic Acid: Conversely, other medications may decrease the renal excretion rate of gadopentetic acid. This could lead to higher serum levels and a prolonged residence time of the contrast agent, theoretically increasing the risk of gadolinium-related toxicity. Examples of drugs in this category include non-steroidal anti-inflammatory drugs (NSAIDs) like aceclofenac and antipyrine, as well as the common analgesic acetaminophen.[1]
• Clinical Significance: It is important to note that while numerous potential interactions are listed in databases, most are classified as "moderate" and are based on theoretical pharmacokinetic principles rather than on extensive clinical outcome data.[51] Some sources note no severe or serious interactions.[47] The primary clinical recommendation is to be aware of the potential for interaction and to monitor patients accordingly, especially those with underlying renal insufficiency.

Interacting Drug/Class	Potential Effect	Mechanism	Clinical Recommendation/Significance	Source(s)
NSAIDs (e.g., Aceclofenac)	May decrease the excretion of gadopentetic acid, increasing its serum level and prolonging its half-life.	Competition for renal excretion pathways.	Moderate interaction. Caution and monitoring are advised, particularly in patients with borderline renal function.	1
Various Renally-Cleared Drugs (e.g., Abacavir, Warfarin, Salbutamol)	Gadopentetic acid may decrease the excretion of these drugs, increasing their serum levels and potential for toxicity.	Competition for renal excretion pathways.	Moderate interaction. Monitor for signs of toxicity related to the co-administered drug.	1
All Drugs	No specific interactions have been identified that would absolutely preclude co-administration.	N/A	General clinical caution is advised. No severe or serious interactions are documented in major drug interaction databases.	47

X. Regulatory History and Global Status

A. Timeline of Key Regulatory Actions

The regulatory history of gadopentetic acid mirrors the evolving understanding of its safety profile, marked by an initial period of widespread use followed by a series of increasingly stringent warnings and restrictions.

• 1987–1988: Gadopentetic acid, as Magnevist®, receives its initial marketing authorizations, including approval from the U.S. FDA, becoming the first gadolinium-based contrast agent available for clinical use.[6]
• 2006–2007: Following the identification of a definitive link between GBCAs and Nephrogenic Systemic Fibrosis (NSF), the FDA issues its first safety alerts. In 2007, the agency requires a Boxed Warning about the risk of NSF to be added to the labeling of all GBCAs, including Magnevist®.[38]
• 2010: The FDA updates and strengthens the Boxed Warning. The new warning explicitly contraindicates the use of the agent in patients with severe kidney disease and acute kidney injury and mandates that all patients be screened for renal dysfunction prior to administration.[5]
• 2017: The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA), acting on concerns about both NSF and the newly discovered phenomenon of gadolinium retention in the brain and other tissues, recommends the suspension of marketing authorizations for all intravenous linear GBCAs, including gadopentetic acid. The committee concluded that the risks of these less stable agents outweighed their benefits when safer, more stable macrocyclic alternatives were available.[15]
• 2017–2018: The FDA conducts its own review of gadolinium retention. While acknowledging the phenomenon, the agency concludes that no definite adverse health effects have been established in patients with normal renal function. Instead of restricting use, the FDA requires a new class-wide warning about retention, mandates the distribution of a patient Medication Guide with each dose, and obligates all GBCA manufacturers to conduct further human and animal safety studies.[34] The EMA's suspension of intravenous gadopentetic acid becomes effective in February 2018.[15]

B. Divergent Global Status: USA vs. EU

The different actions taken by the two leading global regulatory bodies have resulted in a divergent status for gadopentetic acid.

• United States: Gadopentetic acid (Magnevist®) remains legally available for use. However, its clinical application is heavily restricted by the stringent FDA Boxed Warning for NSF and the class-wide warning for gadolinium retention. The U.S. regulatory approach is one of risk management, placing the onus on the prescribing physician to perform meticulous patient screening, conduct a careful risk-benefit analysis, and obtain informed consent.[35]
• European Union: The marketing authorization for the intravenous formulation of gadopentetic acid has been suspended. It is no longer available for systemic use in MRI. An exception was made for the intra-articular formulation, which can still be used for joint imaging (arthrography) because the dose administered is extremely low and systemic exposure is minimal.[15] The EU approach reflects the precautionary principle, prioritizing the elimination of a potential risk by removing higher-risk products from the market when safer alternatives are readily available.

This regulatory divergence is not the result of a disagreement on the underlying scientific evidence—both agencies acknowledge the higher risks of linear agents—but rather a fundamental difference in regulatory philosophy and tolerance for risk. The FDA's risk management strategy trusts clinicians to use a potentially dangerous tool safely in appropriate circumstances, whereas the EMA's precautionary approach removes the tool to prevent any possibility of harm. This provides a compelling real-world case study in how different regulatory cultures can interpret the same scientific data to arrive at starkly different public health policies, with significant consequences for medical practice and manufacturer liability across the globe.

XI. Conclusion: Re-evaluating the Risk-Benefit Profile of a Legacy Agent

A. Synthesis of Findings: The Legacy of a Pioneering but Problematic Agent

Gadopentetic acid holds a unique and complex place in the history of medicine. As the first-in-class gadolinium-based contrast agent, it was a pioneering product that revolutionized diagnostic imaging, transforming MRI from a modality with often limited contrast into a powerful tool for visualizing and characterizing disease.[6] For nearly two decades, it was a cornerstone of neuroradiology and body imaging. However, this legacy of innovation is now inextricably linked to a legacy of significant, late-discovered harm. The story of gadopentetic acid serves as a quintessential case study in pharmacovigilance, powerfully demonstrating that the full safety profile of a novel drug or medical device may only become apparent after years or even decades of widespread post-marketing use. Its history underscores the critical importance of long-term surveillance and the need for humility when introducing new technologies into the human body.

B. The Shifting Risk-Benefit Calculus

The risk-benefit balance for gadopentetic acid has not been static; it has shifted dramatically over time with the accumulation of safety data. The discovery of its causal role in Nephrogenic Systemic Fibrosis (NSF) was the first major blow, transforming it from a seemingly safe, universally applied agent into one that is strictly contraindicated in a large and vulnerable population of patients with renal disease. The subsequent discovery of long-term gadolinium retention in the brain, bone, and other organs—even in patients with normal renal function—has cast a further shadow over its use. This finding, coupled with the direct link between its linear structure and higher risk, has led to a decisive clinical and regulatory preference for the demonstrably safer, more stable macrocyclic GBCAs.[15] In the modern context, where safer alternatives exist for virtually all its indications, the justification for using a higher-risk linear agent like gadopentetic acid has become exceptionally narrow.

C. Recommendations for Clinical Practice

Based on the comprehensive body of evidence, current best-practice recommendations for the use of gadopentetic acid (in jurisdictions where it remains available) are clear and must be strictly followed:

• Adherence to Warnings and Screening: Meticulous adherence to the FDA Boxed Warning is paramount. This includes screening all patients for renal dysfunction prior to administration, which involves inquiring about a history of renal disease and, for at-risk patients (e.g., age >60, hypertension, diabetes), estimating the GFR through laboratory testing.[5]
• Prioritize Safer Alternatives: Gadopentetic acid and other high-risk linear GBCAs should only be considered when the essential diagnostic information cannot be obtained with a non-contrast MRI or with the use of a safer, low-risk macrocyclic GBCA.[5]
• Minimize Exposure: If its use is deemed absolutely necessary, the lowest effective dose that provides adequate diagnostic information should be administered. Repeated administrations should be avoided, and a sufficient period of time must be allowed for drug elimination before any re-administration is contemplated.[37]
• Informed Patient Consent: Clinicians have an ethical and legal obligation to engage in a thorough informed consent discussion with patients regarding the specific risks of the chosen agent, including the potential for both NSF (in relevant populations) and long-term gadolinium retention.[25]

D. Future Perspectives: The Post-Linear GBCA Era

The decline and regulatory restriction of linear agents like gadopentetic acid have catalyzed a permanent shift in the contrast media market. Clinical practice has largely moved into a "post-linear GBCA era," with a clear preference for macrocyclic agents.[15] The safety concerns raised by gadopentetic acid have also spurred crucial innovation. This is proceeding along two main fronts: first, the development of new, "high-relaxivity" macrocyclic agents, which are designed to provide equivalent or superior diagnostic enhancement at a significantly lower dose of gadolinium, thereby minimizing patient exposure.[33] Second, it has reinvigorated the long-standing but still unfulfilled quest for effective, non-gadolinium-based MRI contrast agents, with candidates based on other paramagnetic metals like manganese or iron under active investigation.[33] Therefore, the ultimate legacy of gadopentetic acid is a dual one: it lies not only in the millions of diagnostic images it helped create but also in the more rigorous safety standards and new frontiers of research that its failures have compelled the entire field of medical imaging to pursue.

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