In addition, experiments were done /in rats/ to clarify the in vivo metabolism of gadodiamide (NaCa DTPA-BMA). Results show small quantities of transchelated forms of NaCa DTPA-BMA in urine. HPLC analysis demonstrated these metabolites were the Zn and Cu forms of the drug, resulting from displacement of the Ca ion in the NaCa DTPA-BMA molecule by endogeneous Zn or Cu. Further analyses by HPLC and ICP-AES demonstrate that the unchanged parent drug, the Zn and the Cu forms occur in relative quantities of approximately 92%, 7%, and 1%, respectively. This demonstrates that the Ca ion in caldiamide sodium can be replaced by Zn or Cu ions in vivo, but only to a small extent.
IDENTIFICATION AND USE: Gadodiamide is a contrast agent for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. HUMAN EXPOSURE AND TOXICITY: The possibility of a reaction, including serious, life threatening, fatal, anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered especially in those patients with a known clinical hypersensitivity, a history of asthma, or other allergic respiratory disorders. Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Inadvertent intrathecal use of Omniscan has occurred and caused convulsions, coma, sensory and motor neurologic deficits. Following 1157 gadodiamide-enhanced examinations, measured serum calcium spuriously dropped from 8.65 to 8.33 mg/dL and 34 patients had spurious critical hypocalcemia (<6 mg/dL). Of 60 patients with high-dose gadodiamide injection and renal insufficiency, 36.7% had spurious critical hypocalcemia immediately post MRI. In 216 patients with renal insufficiency, the mean serum magnesium level increased slightly from 1.69 to 1.77 mEq/L following gadodiamide injection. ANIMAL STUDIES: Gadodiamide injection has been shown to have a remarkably low acute lethal toxicity, superior to that of gadopentetate dimeglumine injection or gadoterate meglumine. In comparison with gadopentetate dimeglumine injection, gadodiamide injection had fewer effects on cardiovascular and hemodynamic function after rapid iv injection in anesthetized dogs. Similar to all known iv administered diagnostic imaging agents, gadodiamide injection produces vacuolization of the proximal tubular cells in the kidney, without any change in renal function. The vacuolization was only moderate in degree and was shown to have regressed partially during the 7 days after administration. Gadodiamide injection produced no significant irritation when administered by a variety of intravascular and extravascular routes. In monkeys, administration of gadodiamide daily for 28 days had no effect on the kidney . The compound was well tolerated in monkeys for 28 consecutive days. In rats, significant toxicity occurred only at high doses, particularly in male animals, and the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism. Studies in rabbits showed that gadodiamide at doses 5 times the maximum recommended human dose increased the incidence of skeletal and visceral abnormalities in the offspring. Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits that is observed as an increased incidence of flexed appendages and skeletal malformations administered for 13 days during gestation (approximately 2 times the maximum human cumulative dose) . Skeletal malformations may be due to maternal toxicity since the body weight of the dams was significantly reduced in response to gadodiamide administration during pregnancy. The results of the following genotoxicity assays were negative: bacterial reverse mutation assay, CHO/HGPRT forward mutation assay, CHO chromosome aberration assay, and the in vivo mouse micronucleus assay.
... Urine and serum profiles were monitored for 24 days after iv injections of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide in high doses (4.59 mmol/kg body weight) in rats that received a weekly intraperitoneal (ip) injection of cisplatin (1 mg/kg) for 10 weeks. There were 10 rats in each group. ... Light and electron microscopy showed severe morphologic changes, including tubular dilatation, atrophy, and necrosis induced by cisplatin; however, the contrast media did not induce any additional morphologic changes. Gadopentetate dimeglumine, diatrizoate, and iohexol significantly increased (3-20 times) albuminuria compared with iv saline in cisplatin nephropathy, whereas gadodiamide did not. Albuminuria was highest after diatrizoate injection. All four contrast media caused an immediate and transient significant increase in the excretion of the brush border enzymes alkaline phosphatase and gamma-glutamyltransferase (125-500 times) and the cytoplasmatic enzymes alanine aminopeptidase and lactate dehydrogenase (16-100 times). Compared with saline, the ionic agents significantly increased the excretion of both glucose (two times) and sodium (three to five times), whereas the nonionic agents did not. /The authors concluded that/ high doses of radiologic and magnetic resonance contrast agents cause temporary dysfunction in rats with cisplatin nephropathy. Gadodiamide caused the least dysfunction and diatrizoate the most.
... /The case of/ a 54-year-old woman in whom a /spuriously/ "critically low" serum calcium level was measured with standard colorimetric assay after gadodiamide-enhanced magnetic resonance imaging /is reported/. The same phenomenon was noted in 2 other patients ... Repeat serum calcium measurements performed several hours later were within normal limits. Commercially available gadolinium-based contrast agents might precipitate critically low serum calcium values when measured by standard colorimetric assay. Physician awareness of gadodiamide-induced spurious hypocalcemia might prevent unnecessary therapeutic interventions.
... A case in which a 78-year-old man had a /spuriously/ "critically low" serum calcium level measured with use of standard colorimetric assay after gadodiamide administration during magnetic resonance angiography /is reported/. Reanalysis of the same serum specimen using absorption spectroscopy revealed normal calcium values, confirming the diagnosis of spurious hypocalcemia.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
The objective of this study was to determine the gadolinium (Gd) concentration remaining in human bone tissue after administration of standard clinical doses of 2 Gd-based contrast agents: ProHance and Omniscan. After administration of 0.1 mmol/kg of Gd chelate to patients undergoing hip replacement surgery, bone specimens were collected and analyzed, and compared with an age-matched control population without a history of Gd chelate administration. Bone specimens were collected fresh, refrigerated, and subsequently frozen. After grinding and freeze-drying, tissue digestion was performed using Teflon bombs and concentrated nitric acid. A method for analysis of Gd in bone specimens was developed and validated using inductively coupled plasma mass spectroscopy (ICP-MS). Results were compared with a previous study using a different technique for analysis of the same tissue specimens. Tissue retention was 1.77+/-0.704 microg Gd/g bone (n=9) for Omniscan and 0.477+/-0.271 microg Gd/g bone (n=10) for ProHance measured by ICP-MS. These findings confirmed results from the previous ICP-AES study. Omniscan (Gd[DTPA-BMA]) left approximately 4 times (previous study 2.5 times) more Gd behind in bone than did ProHance (Gd[HP-DO3A]).
Twenty-seven patients--nine with severely reduced renal function (glomerular filtration rate, 2-10 mL/min), nine undergoing hemodialysis, and nine undergoing continuous ambulatory peritoneal dialysis--were followed up for 5, 8, and 22 days, respectively, after receiving gadodiamide injection (0.1 mmol per kilogram body weight). Gadodiamide injection caused no changes in renal function. In patients with severely reduced renal function, the elimination half-life of gadodiamide injection was prolonged (34.3 hours +/- 22.9) compared with data in healthy volunteers (1.3 hours +/- 0.25). An average of 65% of the gadodiamide injected was eliminated during a hemodialysis session. After 22 days of continuous ambulatory peritoneal dialysis, 69% of the total amount of gadodiamide was excreted; this reflects the low peritoneal clearance. In all patients, no metabolism or transmetallation of gadodiamide was found. ...
The pharmacokinetic behavior of gadodiamide was consistent with its extracellular distribution. ... Gadodiamide was shown to be excreted rapidly, primarily through the kidneys. In rats, 94% of the administered dose was excreted in the urine within the first 24 hours after administration. Approximately 1% to 4% appeared in the feces during the same period.
... /In rats/ following iv dosing of gadodiamide (NaCa DTPA-BMA) (0.015 mmol/kg) in a (14)C-labeled form, plasma concentrations of the drug declined rapidly with an elimination half-live of 0.31 hr, a distribution volume of 244 mL/kg and a plasma clearance of 9.2 mL/min/kg. These results demonstrate that NaCa DTPA-BMA distributes into the extracellular fluid compartment and is renally excreted via glomerular filtration. Of the dose of radioactivity given, 86.6% was excreted in urine by 4 hr after injection, and 95.3% in urine and 3.3% in feces by 120 hr. ...
