Adipiodon

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.4X10+4(SRC), determined from a structure estimation method(2), indicates that iodipamide is expected to be immobile in soil(SRC). However, the estimated pKa of iodipamide is 1.44(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Iodipamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Iodinated X-ray contrast agents are considered nondegradable by microorganisms(6).

AQUATIC FATE: Iodipamide is not expected to adsorb to suspended solids and sediment based upon anionic nature of this compound. The estimated pKa of iodipamide is 1.44(1), indicating that this compound will exist primarily as an anion in the aqueous environment and anions do not volatilize from water. According to a classification scheme(2), an estimated BCF of 10(SRC), from an estimated log Kow of 5.16(3) and a regression-derived equation(4), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Iodinated X-ray contrast agents are considered nondegradable by microorganisms(5).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), iodipamide, which has an estimated vapor pressure of 1.1X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase iodipamide may be removed from the air by wet or dry deposition(SRC). Iodipamide does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of iodipamide can be estimated to be 1.4X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that iodipamide is expected to be immobile in soil. The estimated pKa of iodipamide is 1.13(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not inadvertently administered intrathecally.

/CASE REPORTS/ A 73 year old patient with a chronic cholangitis developed protracted anaphylactic shock after intravenous injection of methylglucamine iodipamide. The post-mortem examinations showed no evidence for septicemia. Although endotoxin-shock cannot be completely excluded, the most likely cause of death was an allergic reaction.

/CASE REPORTS/ There have been only two reports of severe hepatotoxic reaction caused by meglumine iodipamide. Lately we experienced such a reaction in an 66-year old female with chronic intrahepatic cholestasis. After drip infusion cholangiography was performed by infusing 40 ml. of 50% meglumine iodipamide (Biligrafin) intravenously, the patient developed nausea and abdominal pain. Her serum transaminase rose to more than 2,000 K-A units on the third day and gradually returned to normal by the 18th day. The macrophage migration inhibition test of her blood was positive for meglumine iodipamide. Accordingly some delayed type of hypersensitivity in the above reaction could be considered. When a larger amount than a recommended dose of meglumine iodipamide is infused in cholangiography, a severe hepatotoxic reaction might be induced, especially in icteric cases.

/CASE REPORTS/ Linear densities which were thought to represent meglumine iodipamide were seen in the renal papillary tubules of three patients for respectively four, six and nine days following intravenous cholangiography (IVC). All three patients were children with hepato-biliary disease. Two patients had biliary roundworm infestation, and one patient had hepatic dysfunction and intestinal ascariasis with possible biliary involvement. Haematuria and renal enlargement were seen in one patient, but the cholangiogram was not conclusively implicated as a cause. This renal tubular "sludging" of biliary contrast medium is recorded because of its potential nephrotoxic significance. The possible causes are discussed.

/CASE REPORTS/ Two cases of meglumine iodipamide (Cholografin) hepatotoxicity were confirmed by liver biopsy. The hepatic lesion was centrilobular in location and resolved within a short period of time. Nausea and vomiting commonly reported after intravenous cholangiography may be clinical manifestations of this entity.

PURE CULTURE: Iodinated X-ray contrast agents are considered nondegradable by microorganisms(1,2). However when incubated with 1 mM iodipamide at 30 °C for 32 days, the fungus Trametes versicolor has been shown to partially diiodinate C-14 ring-labeled iodipamide but the iodide release was a very small amount of that calculated for complete deiodination(1).

An estimated BCF of 10 was calculated in fish for iodipamide(SRC), using an estimated log Kow of 5.16(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The estimated pKa of iodipamide is 1.44(1), indicating that this compound will primarily exist as an anion in the aqueous environment and anions do not volatilize from water or moist soil surfaces. Iodipamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-24 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ...The present study was designed to assess the hepatotoxic potential of this drug in rats. Iodipamide administered intraperitoneally or intravenously caused a characteristic type of necrosis which began in the midzonal area and spread to the centrilobular region. Only rats weighing 400 g or more developed necrosis when the dose administered was 2 mmol/kg. Rats weighing 200 g failed to develop liver necrosis even when given 3 mmol/kg. Selenium deficiency and pretreatment with 3-methylcholanthrene protected against liver necrosis due to iodipamide. Phenobarbital pretreatment provided little or no protection. Kidney tubular necrosis was also observed but occurred in young rats and in selenium-deficient rats which developed no liver necrosis. These results indicate that iodipamide is a hepatotoxin in rats. There are a number of factors, age being the most striking, that modify its hepatotoxicity.

FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. ...

... It is also contraindicated in patients with concomitant severe impairment of renal and liver function.

Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially.

Iodated diagnostic contrast agents such as iodipamide are very persistent in aquatic environments(1). Iodipamide is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Iodipamide does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to iodipamide may occur through dermal contact with this compound at workplaces where iodipamide is produced or used. Use data indicate that limited general population exposure to iodipamide will be via administration of pharmaceutical products containing iodipamide. (SRC)

While data specific to iodipamide were not located(SRC, 2012), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including iodipamide meglumine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Iodipamide meglumine/

MEDICATION

Medicine (X-ray contrast medium)

From benzoic acid by (1) nitration to 3-nitrobenzoic acid, (2) reduction by means of stannous chloride or other reducing agent to 3-aminobenzoic acid, (3) iodination with iodine monochloride in acetic acid to the 2,4,6-triiodo derivative, or (4) acylation of the amino group with adipoyl chloride.

Preparation: Priewe, Rutkowski, US 2776241 (1957 to Schering AG)