Diatrizoate: A Comprehensive Monograph on a Foundational High-Osmolality Iodinated Radiocontrast Agent

I. Executive Summary

Diatrizoate, also known by the chemical name amidotrizoate, is a foundational small-molecule diagnostic agent that has been a cornerstone of radiological imaging for decades. Approved for medical use in the United States in 1954, it represents one of the first-generation ionic, high-osmolality iodinated radiocontrast agents.[1] Its primary and essential function is to enhance the visibility of internal anatomical structures, fluids, and pathologies during X-ray-based diagnostic procedures, including conventional radiography, fluoroscopy, and computed tomography (CT).[1]

The mechanism of action for Diatrizoate is fundamentally physical rather than pharmacological. The molecule's structure incorporates three heavy iodine atoms, which possess a high atomic number and electron density. This configuration allows the compound to effectively absorb, or attenuate, X-ray photons, thereby creating a stark contrast between the agent-filled space and surrounding soft tissues.[2] This property of radiopacity is the basis for its utility in a vast array of diagnostic applications.

Clinically, Diatrizoate is utilized in multiple formulations, most commonly as its highly water-soluble sodium and meglumine salts, or as a combination of the two.[6] This versatility allows for administration via several routes—including oral, rectal, intravenous, and direct instillation—enabling the visualization of the gastrointestinal tract, the urinary system, blood vessels, and other body cavities.[1] It serves as a critical alternative to barium sulfate for gastrointestinal studies in cases of suspected perforation.[1]

Despite its long-standing utility, the defining characteristic of Diatrizoate is its high osmolality, which is significantly greater than that of human plasma.[1] This physical property is directly responsible for a spectrum of physiological effects and potential adverse reactions, most notably the risk of fluid shifts leading to dehydration and hypovolemia, particularly in vulnerable populations such as infants and the elderly.[9] Its hypertonicity also underlies a critical contraindication with the anti-diabetic medication metformin, where the potential for contrast-induced nephropathy can lead to life-threatening lactic acidosis.[1] In recognition of its fundamental importance to global health, particularly in resource-limited settings, Diatrizoate is included on the World Health Organization's List of Essential Medicines.[1]

II. Chemical and Pharmaceutical Profile

The efficacy, safety, and clinical utility of Diatrizoate are intrinsically linked to its unique molecular structure and physicochemical properties. A detailed understanding of its chemistry is essential for appreciating its function as a contrast agent.

Nomenclature and Identification

Diatrizoate is identified by a consistent set of chemical names and international identifiers, ensuring its unambiguous recognition in scientific literature, regulatory filings, and clinical practice.

• Systematic (IUPAC) Name: 3,5-Bis(acetylamino)-2,4,6-triiodobenzoic acid.[1]
• Common Names and Synonyms: Diatrizoic acid, amidotrizoic acid, amidotrizoate.[1]
• DrugBank Identification: The compound is cataloged under DrugBank Accession Number DB00271 as a small molecule drug.[1]
• CAS Registry Number: The parent acid form is registered under CAS Number 117-96-4.[10] Its clinically relevant salt forms have distinct identifiers (see below).
• Anatomical Therapeutic Chemical (ATC) Code: Diatrizoate is classified under the ATC code V08AA01, which designates it as a water-soluble, nephrotropic, high-osmolar X-ray contrast medium.[1]

Molecular Structure and Physicochemical Properties

The molecular architecture of Diatrizoate is a deliberate and effective design for its diagnostic purpose. Its structure is a derivative of benzoic acid, a common and stable scaffold in medicinal chemistry. The core structure is a benzene ring substituted with a carboxyl group ().[11]

The key functional components are the three iodine atoms covalently bonded to the ring at the 2, 4, and 6 positions. It is the high atomic mass and electron density of these iodine atoms that confer the molecule's radiopaque properties.[4] To render this otherwise lipophilic core soluble in water for clinical administration, two hydrophilic acetamido (

) groups are attached at the 3 and 5 positions, flanking the iodine atoms.[11] The combination of the carboxyl group and the acetamido groups ensures high water solubility, a critical requirement for a diagnostic agent administered in aqueous solution.

• Molecular Formula: .[10]
• Molecular Weight: Approximately 613.92 g/mol for the acid form.[10]
• Physical Appearance: It is a white to off-white solid crystalline powder.[11]
• Solubility: The acid form is highly soluble in water, with a reported solubility of 500 g/L at 25°C. It is also soluble in methanol.[11] Its salt forms are even more water-soluble.
• Stability: The compound is known to be light-sensitive and should be stored in a dark place.[1]

Formulations and Commercial Preparations

In clinical practice, Diatrizoic acid is not used directly. Instead, it is administered as one of two primary water-soluble salts: Diatrizoate sodium or Diatrizoate meglumine. Many commercial products are formulated as fixed-ratio combinations of these two salts to leverage their distinct properties.[6]

The selection of the salt form is a critical aspect of pharmaceutical formulation. While both salts deliver the same radiopaque anion (diatrizoate), the cation (sodium vs. meglumine) significantly influences the solution's characteristics. Sodium is a small, inorganic cation, while meglumine (N-methyl-D-glucamine) is a larger, organic cation derived from sorbitol. For a given concentration of iodine, solutions of meglumine salts are generally less hyperosmolar and exhibit lower rates of certain adverse effects compared to the corresponding sodium salts. However, they are also more viscous. By creating combination products, manufacturers can engineer a formulation that balances osmolality, viscosity, and iodine concentration to optimize the agent for specific diagnostic procedures and enhance patient tolerance. This represents a foundational example of using salt engineering to improve a drug's performance and safety profile.

• Diatrizoate Sodium: Registered under CAS Number 737-31-5.[1]
• Diatrizoate Meglumine: Registered under CAS Number 131-49-7.[7]
• Commercial Products: A wide range of brand names exist, including Gastrografin®, Hypaque®, Renovist®, MD-Gastroview®, and Cystografin®.[1] Gastrografin®, a widely used oral/rectal solution, is a combination product containing 660 mg/mL of diatrizoate meglumine and 100 mg/mL of diatrizoate sodium.[13]
• Excipients: Formulations intended for oral or rectal administration, such as Gastrografin®, contain various inactive ingredients, including flavoring agents, sweeteners (saccharin sodium), surfactants (polysorbate 80), and anti-foaming agents (simethicone) to improve palatability and administration.[15] The presence of these excipients makes such formulations strictly unsuitable for intravascular injection.[1]

Synthesis and Manufacturing Process

The chemical synthesis of Diatrizoic acid is a multi-step process that efficiently builds the complex, functionalized molecule.[11] The process begins with a readily available starting material, 3,5-Dinitrobenzoic acid.

1. Reduction: The two nitro groups on the starting material are reduced to amino groups using a catalyst such as Raney nickel or palladium on carbon, yielding 3,5-diaminobenzoic acid.[1]
2. Iodination: This is the critical step for incorporating the radiopaque element. The 3,5-diaminobenzoic acid is reacted with an iodinating agent like iodine monochloride () in an acidic medium. This reaction introduces three iodine atoms onto the most activated positions of the benzene ring, resulting in 3,5-diamino-2,4,6-triiodobenzoic acid.[11]
3. Acylation: The final step involves the acylation of the two amino groups. The intermediate is treated with acetic anhydride, which converts the amino groups into acetamido groups, yielding the final product, 3,5-diacetamido-2,4,6-triiodobenzoic acid (Diatrizoic acid).[1]
4. Salt Formation: The resulting acid is then neutralized with an appropriate base, such as sodium hydroxide or meglumine, to produce the desired clinically used salt form.[11]

Table 1: Physicochemical Properties of Diatrizoic Acid and its Salts

Parameter	Diatrizoic Acid	Diatrizoate Sodium	Diatrizoate Meglumine
CAS Number	117-96-4 10	737-31-5 1	131-49-7 7
Molecular Formula	12	15	7
Molecular Weight (g/mol)	613.92 10	635.90 15	809.13 7
Water Solubility	500 g/L (25°C) 11	High	High
Organically Bound Iodine (%)	62.0% (calculated)	59.9% 15	47.1% 15

This table highlights the differences between the parent acid and its clinically utilized salt forms. Notably, the percentage of organically bound iodine, the active component for radiocontrast, varies significantly. This difference is due to the varying molecular weights of the counter-ions (sodium and meglumine). This has direct implications for formulation and dosing, as a larger mass of the meglumine salt is required to deliver the same amount of iodine as the sodium salt.

III. Clinical Pharmacology

The clinical effects of Diatrizoate are governed by its pharmacodynamic and pharmacokinetic properties. Its mechanism of action is physical, while its movement through and elimination from the body dictates its specific diagnostic applications.

Pharmacodynamics: Mechanism of Radiocontrast

Unlike most therapeutic drugs, Diatrizoate does not exert its primary effect by interacting with biological receptors or modulating enzymatic pathways.[15] Its mechanism of action is classified as a "X-Ray Contrast Activity," a direct consequence of its atomic composition.[18]

The core principle of its function lies in the physics of X-ray attenuation. The three iodine atoms in each Diatrizoate molecule have a high atomic number (Z=53) and a high electron density. When a beam of X-rays passes through the body, these iodine atoms are highly effective at absorbing the X-ray photons, preventing them from reaching the detector or film on the other side.[2] This process of differential absorption creates contrast. Body compartments filled with Diatrizoate, such as the GI tract lumen or blood vessels, become radiopaque (white on a radiograph), allowing them to be clearly distinguished from surrounding soft tissues which are relatively radiolucent (darker on a radiograph). This increased radiodensity is the fundamental basis for its diagnostic utility.[4]

A critical pharmacodynamic characteristic of Diatrizoate is its high osmolality. It is classified as a high-osmolality contrast medium (HOCM).[1] Solutions of Diatrizoate are markedly hypertonic relative to blood plasma (which has an osmolality of approximately 290 mOsm/kg). The osmolality of clinical Diatrizoate solutions can range from approximately 1500 mOsm/kg for a 50% solution to over 2000 mOsm/kg for a 76% solution.[1] This intense osmotic pressure is responsible for many of the agent's secondary physiological effects and adverse reactions, such as fluid shifts, dehydration, and sensations of heat or pain upon injection.[9]

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

The pharmacokinetic profile of Diatrizoate is exceptionally well-suited to its function as a diagnostic agent, demonstrating a clear relationship between the drug's disposition in the body and its clinical applications.

Absorption

The absorption of Diatrizoate is highly dependent on the route of administration and the integrity of biological barriers.

• Oral/Rectal Administration: When administered into a healthy, intact gastrointestinal (GI) tract, Diatrizoate is only minimally or sparingly absorbed into the systemic circulation.[1] This property is paramount to its function as a luminal contrast agent for the GI tract, as it remains largely within the bowel to provide opacification. While absorption is low, it is not zero; small amounts can enter the bloodstream, which may be sufficient to allow for incidental visualization of the urinary tract on delayed images and can interfere with subsequent thyroid function tests.[15]
• Gastrointestinal Perforation: In the event of a breach in the GI wall (perforation), the agent can leak into the peritoneal cavity, from which it is readily absorbed into the systemic circulation.[20] This is a key reason for its use over barium sulfate when perforation is suspected.

Distribution

Once in the systemic circulation (either via intravenous injection or absorption from the peritoneum), Diatrizoate distributes rapidly.

• Intravascular Administration: Following IV injection, Diatrizoate salts quickly distribute throughout the extracellular fluid compartment.[4] They do not significantly cross cellular membranes or the intact blood-brain barrier. The volume of distribution is relatively large, indicating extensive penetration into the interstitial spaces of body tissues.[4]
• Intraluminal (GI) Administration: A major distribution effect following oral or rectal administration is driven by its high osmolality. The hypertonic solution creates a strong osmotic gradient that pulls water from the surrounding tissues and vasculature into the lumen of the bowel. This causes dilution of the contrast medium but is also the mechanism behind its therapeutic use in dislodging impacted meconium.[1]

Metabolism

Diatrizoate is a metabolically inert compound. It is not subject to biotransformation by hepatic enzymes or other metabolic processes in the body.[4] The molecule is excreted from the body chemically unchanged from how it was administered.

Excretion

The elimination of Diatrizoate from the body is efficient and occurs primarily through a single pathway.

• Renal Excretion: The primary route of elimination for systemically absorbed Diatrizoate is via the kidneys.[4] It is freely filtered by the glomeruli and is not significantly reabsorbed or secreted by the renal tubules. It is excreted unchanged in the urine.[21] This rapid and efficient renal clearance is precisely what makes it an effective agent for excretory urography, as the drug becomes concentrated in the renal collecting systems, ureters, and bladder, rendering them visible on radiographs.
• Alternate Excretion: In patients with severe renal impairment, the liver and small intestine provide a major alternative (vicarious) route of excretion for the drug.[21]
• Lactation: Diatrizoate salts are known to be excreted into human breast milk following maternal administration.[22] However, the amount is small, and because the drug is poorly absorbed from the infant's GI tract, the risk to the nursing infant is considered minimal.[16]

The pharmacokinetic journey of Diatrizoate is a clear illustration of how a drug's properties are tailored to its purpose. Its poor oral absorption confines it to the GI tract for luminal imaging. Its rapid, unchanged renal excretion allows it to function as a marker for the urinary system. Its metabolic stability ensures that the iodine-bearing, radiopaque molecule remains intact throughout its transit in the body, guaranteeing its diagnostic efficacy.

IV. Clinical Applications in Diagnostic Imaging

Diatrizoate's unique properties make it a versatile agent with a broad spectrum of applications in diagnostic radiology, as well as select therapeutic uses that leverage its physical characteristics.

Gastrointestinal (GI) Tract Examination

Diatrizoate is widely indicated for the radiographic examination of various segments of the GI tract, including the esophagus, stomach, proximal small intestine, and colon.[9]

• Alternative to Barium Sulfate: Its most critical role in GI imaging is as a water-soluble alternative to barium sulfate. Barium is an inert, insoluble suspension that provides excellent mucosal coating but can cause severe, life-threatening peritonitis if it leaks into the abdominal cavity through a perforation. Diatrizoate, being water-soluble, is absorbed from the peritoneum and excreted by the kidneys, making it the agent of choice in patients with suspected GI perforation, anastomotic leak after surgery, or threatening perforation from peptic ulcers or diverticula.[1] It is also indicated for patients with a known allergy to barium.[1]
• Specific Indications: It is used to diagnose conditions such as partial or complete stenosis, acute hemorrhage, and to delineate the anatomy of gastrointestinal fistulas.[20] It can also be used to visualize foreign bodies or tumors prior to endoscopic procedures.[20]

Computed Tomography (CT)

In modern imaging, Diatrizoate is frequently used as an oral or rectal contrast agent for CT scans of the abdomen and pelvis. When administered, it opacifies the lumen of the bowel. This is essential for distinguishing loops of bowel from adjacent organs, lymph nodes, or pathological structures such as abscesses or tumors, thereby improving the diagnostic accuracy of the scan.[1]

Urogenital System Imaging

Diatrizoate is a classic agent for visualizing the urinary tract.

• Excretory Urography: Following intravenous injection, the agent is rapidly excreted by the kidneys, providing opacification of the renal calyces, ureters, and bladder.[6]
• Retrograde Cystourethrography: The agent can be directly instilled into the bladder via a catheter to evaluate bladder anatomy and detect conditions such as vesicoureteral reflux.[8]

Vascular Imaging (Angiography and Venography)

When administered intravenously or intra-arterially, Diatrizoate opacifies the vascular system, allowing for the visualization of arteries and veins. It has been used for procedures such as angiography, venography, and splenoportography to assess vascular anatomy and pathology.[3] However, due to its high osmolality and associated side effects like pain and heat, its use in intravascular imaging has been largely superseded by newer, better-tolerated low-osmolality and iso-osmolar contrast media.

Other Specialized Imaging

The versatility of Diatrizoate extends to other specialized procedures, including:

• Arthrography: Injection into joint spaces to visualize joint structures.[1]
• Discography: Injection into intervertebral discs to assess disc pathology.[11]

Therapeutic Applications

Interestingly, a primary physical property of Diatrizoate—its high osmolality—which is responsible for many of its side effects, can be harnessed for therapeutic benefit in specific clinical scenarios. This represents a unique dual-purpose application where a diagnostic agent's characteristic is repurposed as a therapeutic mechanism.

• Meconium Ileus: In newborns with uncomplicated meconium ileus, a condition where thick, sticky meconium obstructs the distal ileum, a Diatrizoate enema can be both diagnostic and therapeutic. The hypertonic solution draws a large volume of fluid into the bowel lumen, which hydrates and loosens the impacted meconium, often facilitating its passage and relieving the obstruction without surgery.[1]
• Ascaris lumbricoides Obstruction: Similarly, in cases of intestinal obstruction caused by a large bolus of Ascaris roundworms, oral administration of Diatrizoate can be effective. The agent does not have a direct anthelmintic effect but instead works osmotically. The induced fluid shift into the bowel can help dislodge the impacted mass of worms and relieve the obstruction.[1]

V. Dosage and Administration Guidelines

The safe and effective use of Diatrizoate requires strict adherence to procedure-specific guidelines for dosing, dilution, and administration, with special attention paid to vulnerable patient populations.

Routes of Administration

Diatrizoate's versatility is reflected in its multiple approved routes of administration, each tailored to visualize a specific anatomical region:

• Oral: For examination of the upper GI tract and for bowel opacification in CT.[1]
• Rectal (Enema): For examination of the colon and distal small bowel.[1]
• Intravenous (IV) Injection: For excretory urography and vascular imaging (angiography).[1]
• Intra-arterial Injection: For selective arteriography.[27]
• Direct Instillation: For retrograde cystourethrography via a bladder catheter.[1]

Special Populations

Extreme caution and specific protocols are mandated for pediatric, geriatric, dehydrated, and cachectic (severely debilitated) patients. The primary concern in these groups is the risk of significant fluid shifts caused by the hypertonic agent, which can lead to severe dehydration, hypovolemia, hypotension, and shock.[1]

• Dilution is Mandatory: For oral or rectal use in these at-risk patients, the contrast medium must be appropriately diluted to reduce its osmotic load. For very young children (under 10 kg) and debilitated children, a 1 part Diatrizoate to 3 parts water dilution is recommended.[17]
• Hydration: Ensuring adequate patient hydration before the procedure is critical. In pediatric or severely debilitated patients, maintaining an open intravenous fluid line for potential rehydration is strongly advised.[9]

Table 2: Dosage and Administration Guidelines for Diatrizoate Formulations

Procedure	Patient Population	Route	Recommended Dose & Dilution
Radiographic GI Exam	Adults	Oral	30–90 mL, undiluted 17
	Children (5–10 years)	Oral	60 mL; may be diluted 1:1 with water, milk, or beverage 17
	Infants & Children (<5 years)	Oral	30 mL; may be diluted 1:1. For patients <10 kg or debilitated, dilute 1:3 with water 17
	Adults	Rectal Enema	240 mL diluted in 1,000 mL of tap water 17
	Children (>5 years)	Rectal Enema	90 mL diluted in 500 mL of tap water 17
	Children (<5 years)	Rectal Enema	Dilute 1:5 with tap water 17
CT Body Imaging	Adults	Oral	240 mL of a dilute solution (prepared by diluting 25 mL of Gastrografin® to 1 L with water), administered 15–30 min prior to imaging 17
Excretory Urography	Adults	IV	20 mL; may increase to 40 mL if needed 27
	Children (11–15 years)	IV	16 mL 27
	Children (5–7 years)	IV	12 mL 27
	Infants (6–12 months)	IV	6 mL 27
	Infants (<6 months)	IV	4 mL 27
Aortography	Adults (>16 years)	IV / Intra-arterial	15–40 mL per injection; not to exceed 160 mL total dose 27
Peripheral Arteriography	Adults	Intra-arterial	20–40 mL for whole extremity; 10–20 mL for upper or lower half 27
Retrograde Cystography	Adults	Bladder Instillation	25–300 mL, depending on bladder capacity and irritability 26

This table consolidates the complex dosing information into a practical reference. It underscores the critical importance of adjusting doses and, especially, dilutions based on the patient's age, condition, and the specific diagnostic procedure being performed. This is a key safety measure to mitigate the risks associated with this high-osmolality agent.

VI. Comprehensive Safety Profile

While a highly effective diagnostic tool, Diatrizoate is associated with a well-defined spectrum of adverse effects, contraindications, and warnings, primarily stemming from its high osmolality and iodine content.

Adverse Effects

Adverse reactions can range from mild and transient to severe and life-threatening.

• Common (1% to 10% incidence): The most frequently reported side effects are gastrointestinal, including nausea, vomiting, and diarrhea, particularly after oral administration.[1] Following intravascular injection, a generalized sensation of warmth or flushing is common.[19]
• Hypersensitivity/Anaphylactoid Reactions: These are a significant concern with all iodinated contrast media. Reactions are not typically dose-dependent and can occur unpredictably. They can manifest as mild symptoms such as urticaria (hives), pruritus (itching), skin redness, rash, sneezing, and conjunctivitis.[1] More severe reactions can include angioedema, bronchospasm, respiratory distress, hypotension, and life-threatening anaphylactic shock.[9] Patients with a personal or family history of bronchial asthma, significant allergies (e.g., hay fever, food allergies), or a prior reaction to a contrast agent are at a significantly increased risk.[16]
• Cardiovascular Effects: Transient changes in heart rate and blood pressure can occur.[19] Rarely, more serious events such as tachyarrhythmia, myocardial infarction, and cardiac arrest have been reported, particularly with intravascular administration.[19]
• Renal Effects: Diatrizoate can pose a risk to renal function, a condition known as contrast-induced nephropathy (CIN). This is characterized by an acute decline in renal function following contrast administration. Patients with pre-existing kidney disease, diabetes, or dehydration are at the highest risk.[1]
• Endocrine Effects: The high iodine load from Diatrizoate can affect thyroid function. There are reports of transient thyroid suppression or hypothyroidism, particularly in neonates and infants.[19] The U.S. FDA has issued a specific safety alert regarding this risk in the pediatric population.[32] Conversely, in patients with underlying thyroid disease like multinodular goiter, the iodine load can induce hyperthyroidism or precipitate a thyroid storm.[9]
• Neurological Effects: Although rare, serious neurological adverse events have been reported, primarily with intravascular use. These include seizures, convulsions, and transient disturbances in consciousness.[16]
• Severe Cutaneous Adverse Reactions (SCARs): Very rare but life-threatening skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported from 1 hour to several weeks after intravascular administration.[19]

Contraindications

There are several absolute contraindications for the use of Diatrizoate:

• Hypersensitivity: Known hypersensitivity to Diatrizoate or any of its components is an absolute contraindication.[15]
• Intrathecal Administration: Diatrizoate formulations are NOT FOR INTRATHECAL USE. Inadvertent injection into the spinal canal can cause severe and fatal neurotoxicity, including death, convulsions, cerebral hemorrhage, and paralysis.[32]
• Tracheo-esophageal Fistula: It should not be used to investigate a suspected tracheo-esophageal fistula. If aspirated into the respiratory system, the hyperosmolar solution will cause rapid, massive, and potentially fatal pulmonary edema.[1]
• High-Risk Patients (Undiluted): The administration of undiluted Diatrizoate solution is contraindicated in patients with a high risk of aspiration and in patients with low plasma volume, such as dehydrated newborns, infants, and children, due to the risk of severe hypovolemic complications.[1]
• Manifest Hyperthyroidism: The agent is contraindicated in patients with overt, uncontrolled hyperthyroidism due to the risk of exacerbating the condition.[25]

Warnings and Precautions

• Dehydration and Hypovolemia: This is the most critical warning associated with oral or rectal administration. The hypertonic solution osmotically draws large volumes of fluid into the bowel, which can lead to severe dehydration, hypovolemia, hypotension, and shock. This risk is most pronounced in infants, young children, the elderly, and debilitated patients. Pre-existing fluid and electrolyte imbalances must be corrected prior to administration, and adequate hydration must be maintained.[1]
• Aspiration: Aspiration of the hypertonic solution into the lungs is a medical emergency that can cause severe chemical pneumonitis and life-threatening pulmonary edema. Extreme caution must be exercised in all patients at risk of aspiration, such as those with swallowing disorders or altered mental status.[1]
• Iodine Sensitivity/Allergy: While a history of a seafood allergy or sensitivity to iodine is not an absolute contraindication, it signals an increased risk for a hypersensitivity reaction. Such patients should be managed with extreme caution, and premedication with corticosteroids or antihistamines may be considered.[1]
• Renal Impairment: Use with caution in patients with advanced renal disease, as excretion of the contrast medium may be impaired, increasing the risk of toxicity.[34]
• Thyroid Disease: Caution is required when administering to patients with euthyroid goiter or subclinical hyperthyroidism, as the iodine load can precipitate overt hyperthyroidism or thyroid storm.[9]

VII. Clinically Significant Interactions

The administration of Diatrizoate can lead to several clinically important interactions with other drugs, pre-existing diseases, and laboratory tests. Proper patient management requires awareness of these potential interactions.

Drug-Drug Interactions

There are over 170 drugs known to potentially interact with Diatrizoate, with many classified as major or moderate in severity.[36] The most critical interactions involve medications that affect renal function or thyroid physiology, or those that can complicate the management of a hypersensitivity reaction.

• Metformin: This is a major and widely recognized interaction. If a patient receiving metformin develops contrast-induced nephropathy (CIN) after intravascular Diatrizoate administration, the resulting renal impairment can prevent the excretion of metformin. This can lead to the accumulation of metformin to toxic levels, causing the rare but life-threatening complication of lactic acidosis. To mitigate this risk, clinical guidelines, such as those from the American College of Radiology, recommend temporarily withholding metformin before and for 48 hours after the procedure in patients with pre-existing renal dysfunction or those undergoing certain arterial procedures.[1]
• Aldesleukin (Interleukin-2): Patients who have been treated with aldesleukin have an increased risk of delayed hypersensitivity reactions to iodinated contrast agents.[26]
• Radioactive Iodine (e.g., Sodium Iodide I-131): The large load of stable iodine in Diatrizoate will compete with and block the uptake of radioactive iodine by the thyroid gland. This significantly diminishes the diagnostic and therapeutic efficacy of radioactive iodine procedures for weeks to months following contrast administration. If thyroid imaging or therapy with radioactive iodine is planned, it should be performed before the administration of Diatrizoate.[23]
• Nephrotoxic Drugs: Co-administration of Diatrizoate with other drugs known to be nephrotoxic (e.g., aminoglycoside antibiotics, certain NSAIDs, voclosporin) may potentiate the risk of developing acute kidney injury.[27]
• Beta-blockers (e.g., Propranolol): Patients taking beta-blockers may experience more severe anaphylactoid reactions to contrast media. Furthermore, these reactions may be refractory to treatment with standard doses of epinephrine, complicating emergency management.[16]

Drug-Disease Interactions

Certain pre-existing medical conditions can increase the risks associated with Diatrizoate administration [36]:

• Pheochromocytoma: Intravascular administration of contrast media in patients with pheochromocytoma can provoke a severe, life-threatening hypertensive crisis.
• Multiple Myeloma: Patients with multiple myeloma are particularly susceptible to developing irreversible renal failure following contrast administration, especially if dehydrated.
• Myasthenia Gravis: Iodinated contrast agents can exacerbate the symptoms of myasthenia gravis.
• Congestive Heart Failure: The osmotic load and fluid shifts associated with high-osmolality agents can increase intravascular volume and exacerbate heart failure.
• Asthma and Allergies: As previously noted, a history of asthma or significant allergies is a major risk factor for developing a hypersensitivity reaction.

Drug-Laboratory Test Interactions

Diatrizoate can interfere with specific laboratory tests, primarily those related to thyroid function.

• Thyroid Function Tests: The iodine in Diatrizoate will lead to factitiously elevated results in tests that measure total iodine, such as the protein-bound iodine (PBI) test, and will interfere with radioactive iodine uptake (RAIU) studies for up to a year.[15] It is important to note that modern thyroid function tests that directly measure hormone levels, such as T3 resin uptake and total or free thyroxine (T4) assays, are not affected by the iodine load and can be used reliably after contrast administration.[23]

Table 3: Summary of Clinically Significant Drug and Disease Interactions

Interacting Agent/Condition	Nature of Interaction/Risk	Clinical Management/Recommendation
Metformin	Risk of lactic acidosis if contrast-induced nephropathy (CIN) occurs, leading to metformin accumulation.	Temporarily withhold metformin prior to and for 48 hours after the procedure in at-risk patients (e.g., eGFR <30 mL/min/1.73 ). Re-evaluate renal function before restarting.1
Radioactive Iodine (I-131, I-123)	The iodine load from Diatrizoate blocks thyroidal uptake of radioactive iodine, reducing diagnostic and therapeutic efficacy.	Schedule any necessary radioactive iodine procedures before administering Diatrizoate. Avoid concurrent use for 6-8 weeks or longer.23
Other Nephrotoxic Drugs	Additive or synergistic risk of acute kidney injury (CIN).	Avoid co-administration if possible. Ensure adequate hydration and monitor renal function closely if concurrent use is necessary.27
Aldesleukin	Increased risk of delayed hypersensitivity reactions to contrast media.	Monitor patients with a history of aldesleukin therapy closely for delayed reactions.26
Pre-existing Renal Impairment	Increased risk of CIN and impaired excretion of the contrast agent.	Use with extreme caution. Ensure adequate hydration. Consider alternative imaging modalities.
Pheochromocytoma	Risk of provoking a severe hypertensive crisis with intravascular administration.	Use with extreme caution. Pre-medication with alpha- and beta-blockers may be required. Have antihypertensive medications readily available.
Asthma/Allergies	Major risk factor for hypersensitivity and anaphylactoid reactions.	Take a detailed allergy history. Consider premedication with corticosteroids and/or antihistamines. Ensure emergency resuscitation equipment is available.16

This table provides actionable clinical decision support by highlighting the most critical interactions, explaining the underlying risk, and offering clear guidance on how to manage that risk to ensure patient safety.

VIII. Regulatory and Commercial Landscape

Diatrizoate's long history and fundamental utility are reflected in its widespread regulatory approval and global availability under numerous brand names.

Regulatory Status and History

• U.S. Food and Drug Administration (FDA): Diatrizoate was first approved for medical use in the United States in 1954, making it one of the earliest modern contrast agents.[1] The popular brand name formulation Gastrografin® was approved prior to January 1, 1982.[39] The drug is available as a prescription-only medication and is not a controlled substance.[24] Over the years, numerous generic versions have been approved under Abbreviated New Drug Applications (ANDAs), ensuring continued availability and competition.[35] The FDA continues to perform post-market surveillance for the entire class of iodinated contrast media (ICM). A notable recent action was a 2015 safety labeling update for all ICM products, including Diatrizoate, to warn about the risk of hypothyroidism in young children, demonstrating ongoing regulatory oversight.[33]
• Therapeutic Goods Administration (TGA) of Australia: In Australia, Diatrizoate is available under brand names such as Gastrografin®. The active ingredients are listed as amidotrizoate meglumine and sodium amidotrizoate, which are recognized synonyms for diatrizoate salts.[41] Gastrografin® is listed on the Australian Register of Therapeutic Goods (ARTG) with the registration number AUST R 10684.[42] In the Australian scheduling system, this formulation is classified as "Unscheduled," meaning it can be sold in pharmacies without restriction.[42] The TGA has also been engaged in an International Harmonisation of Ingredient Names (IHIN) project to align Australian ingredient names with international standards.[43]
• World Health Organization (WHO): The inclusion of Diatrizoate on the WHO's List of Essential Medicines underscores its global importance. This designation signifies that it is considered a cost-effective and safe medicine essential for meeting the priority healthcare needs of a population, particularly in basic healthcare systems.[1]

Brand Names and Global Availability

Reflecting its status as a widely used, off-patent drug, Diatrizoate is marketed globally under a multitude of brand names. The specific products available may vary by country and formulation (e.g., oral/rectal solution vs. injectable solution).

• Common Brand Names: Gastrografin®, Hypaque®, Urografin®, Renovist®, MD-Gastroview®, Cystografin®, Renografin®, MD-76R®, and Renocal-76®.[1]

IX. Conclusion and Future Perspective

Diatrizoate stands as a landmark molecule in the history of diagnostic medicine. As a pioneering, first-generation iodinated radiocontrast agent, its development in the mid-20th century revolutionized the ability of clinicians to visualize internal anatomy and pathology, establishing the fundamental principles that would guide the field for over 70 years. Its molecular design—a tri-iodinated benzoic acid core rendered water-soluble by hydrophilic side chains—proved to be a robust and effective blueprint for creating radiopacity in a clinically administrable form.

The primary limitation of Diatrizoate, and the defining characteristic of its class, is its high osmolality. This physical property is the direct etiological source of its most significant adverse effects, including pain on injection, hemodynamic shifts, and the risk of severe dehydration in vulnerable patients. The clinical challenges posed by this hypertonicity were the principal driving force behind decades of subsequent pharmaceutical research and development. The recognition of these osmolality-driven risks led directly to the rational design and synthesis of second-generation low-osmolality contrast media (LOCM) and third-generation iso-osmolar contrast media (IOCM), which now represent the standard of care for most intravascular procedures due to their vastly improved safety and patient tolerance profiles.

Thus, the legacy of Diatrizoate is twofold. First, it remains a clinically indispensable agent for a specific set of indications where its properties are either advantageous or its risks are acceptable. Its use as a water-soluble alternative to barium in suspected gastrointestinal perforation is a critical application that continues to save lives. Furthermore, its high osmolality is uniquely repurposed for therapeutic benefit in conditions like meconium ileus, an elegant example of turning a potential liability into a therapeutic asset.

Second, and perhaps more broadly, Diatrizoate serves as a foundational molecule whose well-characterized limitations were the catalyst for innovation. It is a classic case study in pharmaceutical evolution, where a deep understanding of the shortcomings of a successful drug class directly informed the creation of its safer, more refined successors. A thorough comprehension of the chemistry, pharmacology, and clinical profile of Diatrizoate is therefore essential not only for its safe and effective use today but also for appreciating the remarkable trajectory of progress in the field of diagnostic imaging agents that it helped to launch.

Works cited

1. Diatrizoate - Wikipedia, accessed October 3, 2025, https://en.wikipedia.org/wiki/Diatrizoate
2. What is the mechanism of Diatrizoate Sodium? - Patsnap Synapse, accessed October 3, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-diatrizoate-sodium
3. What is Diatrizoate Sodium used for? - Patsnap Synapse, accessed October 3, 2025, https://synapse.patsnap.com/article/what-is-diatrizoate-sodium-used-for
4. diatrizoate meglumine and diatrizoate sodium - medtigo, accessed October 3, 2025, https://medtigo.com/drug/diatrizoate-meglumine-and-diatrizoate-sodium/
5. What is the mechanism of Meglumin diatrizoate? - Patsnap Synapse, accessed October 3, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-meglumin-diatrizoate
6. Search Results | DrugBank Online, accessed October 3, 2025, https://go.drugbank.com/unearth/q?query=DIATRIZOATE+SODIUM+AND+DIATRIZOATE+MEGLUMINE&searcher=drugs
7. Diatrizoate meglumine | DrugBank Online, accessed October 3, 2025, https://go.drugbank.com/salts/DBSALT000844
8. www.mayoclinic.org, accessed October 3, 2025, https://www.mayoclinic.org/drugs-supplements/diatrizoate-intravenous-route/description/drg-20150982#:~:text=Diatrizoate%20meglumine%20injection%20is%20used,procedures%2C%20such%20as%20retrograde%20cystourethrography.
9. GASTROGRAFIN® (Diatrizoate Meglumine and Diatrizoate Sodium ..., accessed October 3, 2025, https://www.bracco.com/sites/default/files/2023-08/gastrografin-facs-template-25-july-2023.pdf
10. CAS Number 117-96-4 | Diatrizoic Acid - Spectrum Chemical, accessed October 3, 2025, https://www.spectrumchemical.com/cas/117-96-4
11. DIATRIZOIC ACID | 117-96-4 - ChemicalBook, accessed October 3, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9258330.htm
12. Diatrizoate - brand name list from Drugs.com, accessed October 3, 2025, https://www.drugs.com/ingredient/diatrizoate.html
13. gastrografin - [Product Monograph Template - Standard], accessed October 3, 2025, https://pdf.hres.ca/dpd_pm/00065640.PDF
14. Amidotrizoic Acid | CAS 117-96-4 | SCBT - Santa Cruz Biotechnology, accessed October 3, 2025, https://www.scbt.com/p/amidotrizoic-acid-117-96-4
15. Diatrizoate Meglumine and Diatrizoate Sodium Solution USP - DailyMed, accessed October 3, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e9da4d3d-d0ca-44f7-aaeb-ae49c3839775&type=display
16. Diatrizoate (intravenous route) - Side effects & uses - Mayo Clinic, accessed October 3, 2025, https://www.mayoclinic.org/drugs-supplements/diatrizoate-intravenous-route/description/drg-20150982
17. GASTROGRAFIN® Diatrizoate Meglumine and Diatrizoate Sodium Solution USP - DailyMed, accessed October 3, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8c2340e4-2b42-45dc-8fac-9960e8172547
18. pubchem.ncbi.nlm.nih.gov, accessed October 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Diatrizoate#:~:text=As%20diatrizoate%20meglumine%20and%20as,studies%2C%20angiography%2C%20and%20urography.&text=Diatrizoic%20acid%20is%20a%20Radiographic,a%20X%2DRay%20Contrast%20Activity.
19. Diatrizoate Side Effects: Common, Severe, Long Term - Drugs.com, accessed October 3, 2025, https://www.drugs.com/sfx/diatrizoate-side-effects.html
20. Gastrografin gastroenteral solution - Summary of Product ..., accessed October 3, 2025, https://www.medicines.org.uk/emc/product/1126/smpc
21. Diatrizoate: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 3, 2025, https://go.drugbank.com/drugs/DB00271
22. Diatrizoate - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed October 3, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501407/
23. Diatrizoate meglumine and Diatrizoate sodium Solution: Package ..., accessed October 3, 2025, https://www.drugs.com/pro/diatrizoate-meglumine-and-diatrizoate-sodium-solution.html
24. Diatrizoate Use During Pregnancy - Drugs.com, accessed October 3, 2025, https://www.drugs.com/pregnancy/diatrizoate.html
25. DATA SHEET - Medsafe, accessed October 3, 2025, https://medsafe.govt.nz/profs/datasheet/g/Gastrografinoralrectalsusp.pdf
26. Diatrizoate Meglumine (Professional Patient Advice) - Drugs.com, accessed October 3, 2025, https://www.drugs.com/ppa/diatrizoate-meglumine.html
27. Gastrografin, Renocal 76 (diatrizoate meglumine/diatrizoate sodium) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed October 3, 2025, https://reference.medscape.com/drug/gastrografin-diatrizoate-meglumine-diatrizoate-sodium-343770
28. Gastrografin Dosage Guide - Drugs.com, accessed October 3, 2025, https://www.drugs.com/dosage/gastrografin.html
29. Table 2. Dosing of Selected Enteral Contrast Agents According to Product Labeling - ASHP, accessed October 3, 2025, https://www.ashp.org/-/media/assets/drug-shortages/docs/drug-shortages-barium-sulfate-table-2.pdf
30. What are the side effects of Meglumin diatrizoate? - Patsnap Synapse, accessed October 3, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-meglumin-diatrizoate
31. Diatrizoate Meglumine and Diatrizoate Sodium - Memorial Sloan Kettering Cancer Center, accessed October 3, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/diatrizoate-meglumine-and-diatrizoate-sodium
32. Diatrizoate Meglumine-Diatrizoate Sodium: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed October 3, 2025, https://www.rxlist.com/diatrizoate_meglumine-diatrizoate_sodium/generic-drug.htm
33. MD-76R™ (Diatrizoate Meglumine - accessdata.fda.gov, accessed October 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/019292Orig1s010ltr.pdf
34. Diatrizoate Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed October 3, 2025, https://www.drugs.com/dosage/diatrizoate.html
35. Label: DIATRIZOATE MEGLUMINE AND DIATRIZOATE SODIUM- diatrizoate meglumine and diatrizoate sodium solution - DailyMed, accessed October 3, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a216a7d5-3c28-482b-956a-93ae146e3763
36. Diatrizoate Interactions Checker - Drugs.com, accessed October 3, 2025, https://www.drugs.com/drug-interactions/diatrizoate.html
37. MD-76 R Interactions Checker - Drugs.com, accessed October 3, 2025, https://www.drugs.com/drug-interactions/diatrizoate,md-76-r.html
38. Diatrizoate/iodipamide Interactions - Drugs.com, accessed October 3, 2025, https://www.drugs.com/drug-interactions/diatrizoate-iodipamide.html
39. Generic Gastrografin Availability - Drugs.com, accessed October 3, 2025, https://www.drugs.com/availability/generic-gastrografin.html
40. MD-76™R - accessdata.fda.gov, accessed October 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019292s010lbl.pdf
41. Gastrografin® (Sodium Amidotrizoate / Amidotrizoate Meglumine) | Radiology Australia, accessed October 3, 2025, https://radiology.bayer.com.au/ctcv/gastrografinr-sodium-amidotrizoate-amidotrizoate-meglumine
42. Gastrografin - NPS MedicineWise, accessed October 3, 2025, https://www.nps.org.au/medicine-finder/gastrografin-liquid
43. International Harmonisation of Ingredient Names (IHIN) - Consultation paper - Therapeutic Goods Administration (TGA), accessed October 3, 2025, https://www.tga.gov.au/sites/default/files/consult-ihin-130515.pdf
44. Meglumine Diatrizoate | C18H26I3N3O9 | CID 8566 - PubChem, accessed October 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/8566
45. diatrizoate - ClinPGx, accessed October 3, 2025, https://www.clinpgx.org/chemical/PA449281
46. DIATRIZOATE SOLN,ORAL - VA Formulary Advisor - VA.gov, accessed October 3, 2025, https://www.va.gov/formularyadvisor/drugs/4001544-DIATRIZOATE-SOLN-ORAL