Gadolinium

GADOLINIUM, ELEMENTAL   CASRN: 7440-54-2

This record contains information for gadolinium in its zero valence state only. For general toxicity and environmental fate of gadolinium ions and gadolinium compounds, refer to the GADOLINIUM COMPOUNDS record; for compound specific information, refer to the appropriate individual records, e.g., gadobenate dimeglumine, etc. For information on the radiological aspects of gadolinium and its compounds, refer to the GADOLINIUM, RADIOACTIVE record. For general toxicological, safety and handling, and environmental information on ionizing radiation emitted from chemical sources including gadolinium, refer to the IONIZING RADIATION RECORD.

For other data, click on the Table of Contents


Human Health Effects:

Emergency Medical Treatment:

Antidote and Emergency Treatment:
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 urs, 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/
[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160] **PEER REVIEWED**

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160] **PEER REVIEWED**

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer�s if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1] **PEER REVIEWED**


Animal Toxicity Studies:


Metabolism/Pharmacokinetics:


Pharmacology:


Environmental Fate & Exposure:


Natural Pollution Sources:
The concentration of gadolinium in the earth's crust is 6.4 ppm(1). As a member of the lanthanide series ranging from atomic number 57 (lanthanum) to 71 (lutetium), gadolinium does not ur in nature in the elemental state and the lanthanides always ur in minerals as mixtures(1). Gadolinium-containing minerals include samarskite, gadolinite, xenotime, as well as other rare earth minerals(2). As gadolinium is found in nature, gadolinium compounds will be released to water and soils as a result of weathering of rocks and soil erosion(SRC).
[(1) Leveque A et al: Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons: Lanthanides. Online Posting date: Jul 13, 2001 http://www.mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/lantsabo.a01/current/pdf as of Sept 25, 2007. (2) O'Neil MJ, ed; The Merck Index. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 767-769 (2001)] **PEER REVIEWED**


Environmental Standards & Regulations:


Chemical/Physical Properties:


Molecular Formula:
Gd
**PEER REVIEWED**


Molecular Weight:
157.25
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**


Color/Form:
Silvery metal; hexagonal
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**

Colorless or faintly yellowish metal; tarnishes in moist air
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 768] **PEER REVIEWED**


Boiling Point:
3273 deg C
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**


Melting Point:
1313 deg C
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**


Density/Specific Gravity:
7.90 g/cu cm
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**


Solubilities:
Soluble in dilute acid
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-63] **PEER REVIEWED**


Vapor Pressure:
5.7X10-10 Pa at 1000 K; 1.54X10-6 Pa at 1200 K; 0.000429 Pa at 1400 K; 0.0279 Pa at 1600 K; 0.618 Pa at 1800 K; 7.39 Pa at 2000 K; 56.2 Pa at 2200 K (calculated)
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-130] **PEER REVIEWED**


Other Chemical/Physical Properties:
VP: 1 Pa at 1563 deg C; 10 Pa at 1755 deg C; 100 Pa at 1994 deg C; 1 kPa at 2300 deg C; 10 kPa at 2703 deg C; 100 kPa at 3262 deg C (calculated from ideal gas hermodynamic functions)
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 6-57] **PEER REVIEWED**

Molar heat capacity: 37.03 J/mol K at 25 deg C, 100 kPa
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 4-127] **PEER REVIEWED**

Standard enthalpy of formation (gas): 397.5 kJ/mol
[Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 5-12] **PEER REVIEWED**

Naturally urring isotopes: 152 (radioactive, abundance: 0.20%); 154 (stable, 2.18%); 155 (stable, 14.80%); 156 (stable, 20.47%); 157 (stable, 15.65%); 158 (stable, 24.84%); 160 (stable, 21.86%); crystalline forms: hexagonal close-packed, alpha-form, density: 7.886, transforms to beta-form at 1262 deg C; body-centered cubic, beta-form exists at >1262 deg C; heat of fusion: 10.05 kJ/mol; heat of sublimation: at 25 deg C: 397.5 kJ/mol
[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 768] **PEER REVIEWED**

Standard reduction potential (Gd3+/Gd): -2.28 V
[Cotton FA et al; Advanced Inorganic Chemistry 6th edition. NY, NY: John Wiley and Sons, p. 1109 (1999)] **PEER REVIEWED**


Chemical Safety & Handling:


Disposal Methods:
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for upational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.
**PEER REVIEWED**


Major Uses:
Neutron shielding ... phosphor activator, catalyst, scavenger for oxygen in titanium production.
[Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 523] **PEER REVIEWED**


Methods of Manufacturing:
(1) Reduction of /gadolinium/ fluoride with calcium, (2) electrolysis of the /gadolinium/ chloride with sodium chloride or potassium chloride in an iron pot that serves as an anode and graphite cathode.
[Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 523] **PEER REVIEWED**


General Manufacturing Information:
Rare earths were not mined domestically in 2006; Import Sources (2002-05): Rare-earth metals, compounds, etc.: China, 76%; France, 9%; Japan, 4%; Russia, 3%; and other, 8%. /Rare earths/
[USGS; Mineral Commodity Summary 2007. Rare Earths. Available from, as of September 25, 2007: http://minerals.usgs.gov/minerals/pubs/commodity/rare_earths/rareemcs07.pdf **PEER REVIEWED**


Formulations/Preparations:
Ingots, lumps, turnings, powder up to 99.9+% pure.
[Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 523] **PEER REVIEWED**


Related HSDB Records:
7537 [GADOLINIUM, COMPOUNDS]


Formulations/Preparations:
Ingots, lumps, turnings, powder up to 99.9+% pure.
[Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 523] **PEER REVIEWED**


Administrative Information:


Hazardous Substances Databank Number: 7536

Last Revision Date: 20080425

Last Review Date: Reviewed by SRP on 1/10/2008

Update History:
Complete Update on 2008-04-25, 16 fields added/edited/deleted
Created 20070523

GADOLINIUM, COMPOUNDS CASRN: NO CAS RN

This record contains general information for gadolinium ions and compounds, including statements in the literature referenced to gadolinium compounds, gadolinium salts, etc. For compound-specific information, refer to the appropriate individual records as listed in the RELATED HSDB RECORDS field; for information on the metal itself, refer to the GADOLINIUM, ELEMENTAL record. For information on the radiological aspects of gadolinium and its compounds, refer to the GADOLINIUM, RADIOACTIVE record. For general toxicological, safety and handling, and environmental information on ionizing radiation emitted from chemical sources including gadolinium, refer to the IONIZING RADIATION RECORD.

For other data, click on the Table of Contents


Human Health Effects:


Human Toxicity Excerpts:
/SIGNS AND SYMPTOMS/ Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD) is a rare fibrosing disorder that urs in patients with renal failure. It is associated with significant mortality and morbidity. Patients typically present with painful or pruritic indurated plaques involving the limbs and trunk, with sparing of the face. Severity and rapidity of cutaneous progression correlate with poorer prognosis. To date, the management of NSF/NFD remains anecdotal. The etiological link in NSF/NFD is also yet to be confirmed, but renal dysfunction seems a common feature. Following recent reports of a possible causative role of gadolinium ... two patients with histologically confirmed NSF/NFD /were presented/, who had exposure to gadolinium-containing contrast agents 1 to 2 months before onset of disease. Severity of renal impairment, lack of immediate dialysis after exposure and cumulative dose of gadolinium are possible factors influencing the development of NSF/NFD. The process of transmetallation of gadolinium chelates may ur in patients with renal impairment, leading to precipitation of free gadolinium in the dermis or other organs, causing tissue injury that ultimately leads to the clinical manifestations of NSF/NFD. Although the causative role is not proven, gadolinium-containing contrast agents should be used only if clearly necessary in patients with renal failure. /Gadolinium-containing contrast agents/
[Lim YL et al; Clin Exp Dermatol 32 (4): 353-8 (2007)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ A case of acute renal failure after administration of gadolinium 0.09 mmol/kg body weight in a patient with preexisting mild renal failure (creatinine clearance 55 mL/min) is described. The additional renal damage was partially reversible. ... The reason for the preexisting renal failure was light-chain disease type kappa. This kind of renal damage may be especially susceptible to contrast media toxicity. /Gadolinium-containing contrast media/
[Jurgensen T et al; Med Klin (Munich) 102 (6): 480-2 (2007)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ ... A case of anaphylactic shock due to gadoterate meglumine (DOTAREM) /is described/. While undergoing a magnetic resonance imaging examination, a 33-year-old nonatopic female patient became severely hypotensive, lost consciousness, and had generalized erythema immediately after the iv injection of this product. She recovered rapidly after she was given injection of epinephrine and her blood volume was restored with intravenous fluids. That DOTAREM had caused this immediate hypersensitivity reaction was proven by the positivity of prick-test and intradermal test at 10-3 (0.37 mg/mL) and in vitro leukocyte histamine release test. The results of these tests indicated that it was the gadoteric acid rather than the meglumine component of DOTAREM that was responsible: positivity of IDR at 10 mg/ml. Skin tests and leukocyte histamine release test to gadopentetate dimeglumine (MAGNEVIST) were negative. In addition of the exceptional character, this observation provides evidence for an immediate hypersensitivity without cross reactivity with gadopentetate dimeglumine. /Gadoterate meglumine/
[Beaudoin E et al; Allerg Immunol (Paris) 35 (10): 382-5 (2003)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ ... a case of serious adverse reaction following the administration of Gd-DTPA (gadolinium with diethylenetriamine pentaacetic acid) /is described/. The patient showed sneezing and hoarseness when Gd-DTPA was administered for the first time. At the second injection, when hydrocortisone was used in advance to prevent allergic reaction, she lapsed into a pre-shock state and anaphylactic reaction was strongly suggested by the laboratory data. The possibility that Gd-DTPA may cause the severe side effects must be noted. /Gadolinium DTPA/
[Nomura M et al; Nippon Igaku Hoshasen Gakkai Zasshi 53 (12): 1387-91 (1993)] **PEER REVIEWED** PubMed Abstract

/CASE REPORTS/ Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare fibrotic condition that presents in patients with a history of renal disease. The aetiology is unknown, but it has recently been proposed that gadolinium, a paramagnetic contrast agent, may be a trigger of this disease. We report three patients with NSF with a history of use of gadolinium in magnetic resonance angiography a few weeks before the onset of symptoms. In the future, gadolinium should probably be avoided as much as possible in renal insufficiency patients until its role in the development of NSF is clarified. /Gadolinium contrast agents/
[Moreno-Romero JA et al; Br J Dermatol 157 (4): 783-7(2007)] **PEER REVIEWED** PubMed Abstract


Drug Warnings:
Nephrogenic fibrosing dermopathy (NFD) causes thickening and hardening of the skin, often in the extremities, and urs in patients with underlying renal disease. The skin lesions can progress rapidly, sometimes leading to joint immobility and the inability to walk. In May 2006, nephrologists at hospital A in St. Louis, Missouri, reported to CDC and the Missouri Department of Health and Senior Services (MoDHSS) a cluster of NFD among patients treated in their dialysis units. CDC and MoDHSS conducted an investigation to determine the number of affected patients and identify risk factors for NFD. Thirty-three patients with NFD were identified in St. Louis, 28 of whom had been treated at hospital A. A matched case-control study was conducted at the hospital. This report summarizes the preliminary results of that study, which indicated that exposure to gadolinium-containing contrast agents during magnetic resonance imaging (MRI) studies was independently associated with NFD. Clinicians should be aware of the potential for NFD, and when possible, should avoid use of gadolinium-containing contrast agents in patients with advanced renal disease. /Gadolinium-containing contrast agents/
[Centers for Disease Control and Prevention (CDC); MMWR Morb Mortal Wkly Rep 56 (7): 137-41(2007)] **PEER REVIEWED** PubMed Abstract

It is not known to what extent that gadobenate dimeglumine is distributed into human milk. Breast-feeding should be discontinued prior to the administration of gadobenate and should not be restarted until at least 24 hours after the administration of gadobenate. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./ /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Studies indicate that gadoversetamide distributes into rat milk, however, it is unknown if this urs in humans. The manufacturer recommends discontinuing nursing and pumping and discarding breast milk for up to 72 hours after gadoversetamide administration. /Gadoversetamide/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./ /Gadodiamide; Gadopentetate dimeglumine; Gadoteridol; Gadoversetamide//
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Adequate and well controlled studies in humans have not been done. Gadobenate should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Gadolinium-based contrast media are important tools in diagnostic and interventional radiology that are particularly useful in patients with renal insufficiency. Recent reports in which exposure to gadolinium compounds has been linked to the development of nephrogenic systemic fibrosis in this patient population, however, are quite concerning. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, <60 mL/min/1.73 m(2)) to severe (glomerular filtration rate, <15 mL/min/1.73 m(2)) renal disease./Gadolinium-based contrast media/
[Chewning RH, Murphy KJ; J Vasc Interv Radiol 18 (3): 331-3 (2007)] **PEER REVIEWED** PubMed Abstract

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare fibrotic condition that presents in patients with a history of renal disease. The etiology is unknown, but it has recently been proposed that gadolinium, a paramagnetic contrast agent, may be a trigger of this disease. We report three patients with NSF with a history of use of gadolinium in magnetic resonance angiography a few weeks before the onset of symptoms. In the future, gadolinium should probably be avoided as much as possible in renal insufficiency patients until its role in the development of NSF is clarified. /Gadolinium contrast agents/
[Moreno-Romero JA et al; Br J Dermatol 157 (4): 783-7(2007)] **PEER REVIEWED** PubMed Abstract

... A case of serious adverse reaction following the administration of Gd-DTPA (gadolinium with diethylenetriamine pentaacetic acid) /is described/. The patient showed sneezing and hoarseness when Gd-DTPA was administered for the first time. At the second injection, when hydrocortisone was used in advance to prevent allergic reaction, she lapsed into a pre-shock state and anaphylactic reaction was strongly suggested by the laboratory data. The possibility that Gd-DTPA may cause the severe side effects must be noted. /Gadolinium DTPA/
[Nomura M et al; Nippon Igaku Hoshasen Gakkai Zasshi 53 (12): 1387-91 (1993)] **PEER REVIEWED** PubMed Abstract

... A case of anaphylactic shock due to gadoterate meglumine (DOTAREM) /is described/. While undergoing a magnetic resonance imaging examination, a 33-year-old nonatopic female patient became severely hypotensive, lost consciousness, and had generalized erythema immediately after the iv injection of this product. She recovered rapidly after she was given injection of epinephrine and her blood volume was restored with intravenous fluids. That DOTAREM had caused this immediate hypersensitivity reaction was proven by the positivity of prick-test and intradermal test at 10-3 (0.37 mg/mL) and in vitro leukocyte histamine release test. The results of these tests indicated that it was the gadoteric acid rather than the meglumine component of DOTAREM that was responsible: positivity of IDR at 10 mg/ml. Skin tests and leukocyte histamine release test to gadopentetate dimeglumine (MAGNEVIST) were negative. In addition of the exceptional character, this observation provides evidence for an immediate hypersensitivity without cross reactivity with gadopentetate dimeglumine. /Gadoterate meglumine/
[Beaudoin E et al; Allerg Immunol (Paris) 35 (10): 382-5 (2003)] **PEER REVIEWED** PubMed Abstract

... A case of acute renal failure after administration of gadolinium 0.09 mmol/kg body weight in a patient with preexisting mild renal failure (creatinine clearance 55 ml/min) is described. The additional renal damage was partially reversible. ... The reason for the preexisting renal failure was light-chain disease type kappa. This kind of renal damage may be especially susceptible to contrast media toxicity. /Gadolinium contrast agent/
[Jurgensen T et al; Med Klin (Munich) 102 (6): 480-2 (2007)] **PEER REVIEWED** PubMed Abstract

Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra-renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium-related contrast-induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF-gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium-chelate binding may expose tissues to toxic free Gd(3+) and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced chronic kidney disease or end-stage renal disease. /Gadolinium-containing contrast media/
[Perazella MA et al; Semin Dial 20 (3): 179-85 (2007)] **PEER REVIEWED** PubMed Abstract

A case of acute renal failure after administration of gadolinium 0.09 mmol/kg body weight in a patient with preexisting mild renal failure (creatinine clearance 55 mL/min) is described. The additional renal damage was partially reversible. ... The reason for the preexisting renal failure was light-chain disease type kappa. This kind of renal damage may be especially susceptible to contrast media toxicity. /Gadolinium-containing contrast media/
[Jurgensen T et al; Med Klin (Munich) 102 (6): 480-2 (2007)] **PEER REVIEWED** PubMed Abstract

Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra-renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium-related contrast-induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF-gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium-chelate binding may expose tissues to toxic free Gd(3+) and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced chronic kidney disease or end-stage renal disease. /Gadolinium-containing contrast media/
[Perazella MA et al; Semin Dial 20 (3): 179-85 (2007)] **PEER REVIEWED** PubMed Abstract


Populations at Special Risk:
Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra-renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium-related contrast-induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF-gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium-chelate binding may expose tissues to toxic free Gd(3+) and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced chronic kidney disease or end-stage renal disease. /Gadolinium-containing contrast media/
[Perazella MA et al; Semin Dial 20 (3): 179-85 (2007)] **PEER REVIEWED** PubMed Abstract


Probable Routes of Human Exposure:
upational exposure to gadolinium compounds may ur through inhalation with this compound at workplaces where gadolinium is produced or used(SRC). As gadolinium is found in nature, the general public may be exposed to gadolinium compounds via inhalation of ambient air and ingestion of food and water(SRC). Gadolinium complexes (e.g., gadobenate dimeglumine, gadobutrol, gadodiamide, gadopentetic acid, gadoteridol, gadoversetamide, and gadoxetic acid) are used as contrast agents in magnetic resonance imaging (MRI)(1). Individuals undergoing MRI diagnostic procedures using gadolinium complexes will be exposed gadolinium compounds(SRC).
[(1) O'Neil MJ, ed; The Merck Index. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 767-769 (2001)] **PEER REVIEWED**

NIOSH (NOES Survey 1981-1983) has statistically estimated that 1.103 workers (140 of these are female) are potentially exposed to gadolinium oxide in the US(1).
[(1) NIOSH; NOES. National upational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available at http://www.cdc.gov/noes/ as of Feb 8, 2008.] **PEER REVIEWED**


Animal Toxicity Studies:


Non-Human Toxicity Excerpts:
/LABORATORY ANIMALS: Acute Exposure/ Groups of 10 male and 10 female Sprague-Dawley rats were given a single iv injection of gadolinium chloride solution at dosages of 0 (saline vehicle), 0.07, 0.14, and 0.35 mmol/kg. Apart from 1 top-dose female, which died during dosing, 5 rats/sex/ group were necropsied 48 hr postdose, and the remaining 5 rats/sex/group were necropsied 14 days postdose. Macroscopic, hematological, and clinical chemistry analyses were undertaken on all animals that were necropsied. Histopathological examination was undertaken on all organs from high-dose and control animals necropsied 48 hr postdose and on tissues that showed treatment-related changes from all other rats necropsied either 48 hr or 14 days postdose. Major lesions related to gadolinium chloride administration consisted of mineral deposition in capillary beds (particularly lung and kidney), phagocytosis of mineral by the mononuclear phagocytic system, hepatocellular and splenic necrosis followed by dystrophic mineralization, mineralization of the fundic glandular mucosa in the absence of necrosis followed by mucous cell hyperplasia, decreased platelet numbers and increased prothrombin time, and activated partial thromboplastin time. Electron microscopy and x-ray microanalysis of the spleen and liver revealed electron-dense deposits in splenic macrophages, Kupffer cells, and hepatocytes composed of gadolinium, calcium, and phosphate. /Gadolinium chloride/
[Spencer AJ et al; Toxicol Pathol 25 (3): 245-55 (1997)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ 1. Groups of five male and five female CD-1 mice received a single iv injection of gadolinium chloride at dosages of 0 (saline control), 0.05, 0.1 and 0.2 mmol/ kg. All mice were necropsied 48 hr post dose. 2. Plasma analysis showed increases in concentrations of lactate dehydrogenase (both sexes), aspartate aminotransferase and alanine aminotransferase (females only) in the 0.2 mmol/kg group. Cholesterol was elevated at all dosages in both sexes while globulin was raised in both sexes at 0.1 and 0.2 mmol/kg. 3. Histological lesions were present at all dosages and increased in severity in a dose-related fashion. The most common lesions were: mineral emboli in capillaries, accumulation of mineral in the mononuclear phagocytic system, hepatocellular necrosis, and lymphoid depletion, necrosis and mineralisation in the spleen. 4. Such observations are similar to those in rats given gadolinium chloride and should be assessed when evaluating the toxicological profile of gadolinium containing compounds being developed for nuclear magnetic resonance imaging. /Gadolinium chloride/
[Spencer A et al; Hum Exp Toxicol 17 (11): 633-7 (1998)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ ... Gadolinium chloride (GdCl3) reduces pulmonary nitric oxide formation, possibly by interference with stretch-activated cellular calcium influx ... . Exhaled nitric oxide and pulmonary vascular resistance /were measured/ in anesthetised rabbits, and ... the effects of GdCl3 /were compared / with those of an nitric oxide-synthase inhibitor (L-N omega-nitro-arginine methyl ester, L-NAME). Both GdCl3 and L-NAME reduced nitric oxide in exhaled air and increased pulmonary vascular resistance. However, the increase in pulmonary vascular resistance was more pronounced with GdCl3 than with L-NAME. A 50% reduction of exhaled nitric oxide caused by either GdCl3 or L-NAME was accompanied by a 90% or 17% increase in pulmonary vascular resistance respectively. Inhaled nitric oxide (40 ppm) reduced pulmonary vascular resistance after L-NAME, but not after GdCl3 infusion. Infusion of glyceryltrinitrate reduced pulmonary vascular resistance after GdCl3 infusion. GdCl3 caused hypoxemia, probably due to vasoconstriction since lung weight was unaltered. Thus GdCl3 can induce a marked increase in pulmonary vascular resistance, which partly may be caused by inhibition of pulmonary nitric oxide formation. Intact stretch-activated calcium channels may be important for maintenance of normal pulmonary vascular function. /Gadolinium chloride/
[Adding LC et al; Pharmacol Toxicol 83 (1): 8-15 (1998)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ ... 2 experiments were carried out in male Sprague-Dawley rats given a single iv dose of 0.07 mmol/kg GdCl3. Plasma calcium and phosphate concentrations approximately doubled between 30 min and 12 hr postdose but had regressed back to near normal values by 24 hr. However, there were no observable clinical signs in treated animals. Histologically, there was progressive mineralization of the lamina propria of the neck region of the fundic glands from 6 hr postdose, forming a distinctive mineral band by 12 hr postdose. At 7 and 14 days postdose the mineral deposits were accompanied by mucous cell hyperplasia, interstitial fibrosis, and a very sparse infiltration of inflammatory cells. By 56 days postdose only asional mineral deposits remained. Transmission electron microscopy showed mineral first nucleated on collagen in the interstitium, but there was no evidence of cell necrosis. X-ray microanalysis showed that the interstitial mineral was composed of calcium and phosphate in the form of hydroxyapatite; gadolinium (Gd) was only very rarely identified. These findings are consistent with metastatic mineralization. ... /Gadolinium chloride/
[Rees J et al; Toxicol Pathol 25 (6): 582-9 (1997)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ ... A combination of renal ischemia and intrarenal iodinated contrast agent infusion (diatrizoate) led to a reproducible and reversible model of acute renal failure (n = 5). Using this model, the renal tolerance of gadolinium DOTA (Gd-DOTA) (n = 10) and gadolinium DTPA (Gd-DTPA) (n = 10) were evaluated. The effects of the association of Gd-DOTA with diatrizoate (n = 5) on renal function also were assessed. RESULTS. Gadolinium DOTA induced no change in serum creatinine and creatinine clearance. Gadolinium DTPA induced a significant increase in serum creatinine (50 to 83 +/- 5 and 70 +/- 6 u/mol/L) before and at 24 and 48 hours, respectively (P < .05), and a decrease in creatinine clearance from 1.6 +/- 0.1 to 0.8 +/- 0.1; 1.2 +/- 0.1 mL/mL before and at 24 and 48 hours, respectively (P < .05). In this model, Gd-DOTA did not modify the renal tolerance of diatrizoate as assessed with serum creatinine and creatinine clearance. /The authors concluded that/ Gadolinium DOTA is not nephrotoxic and can be infused in association with iodinated contrast media. In this model, Gd-DTPA induced reversible renal failure. /Gadoterate meglumine (gadolinium DOTA) and gadolinium DTPA/
[Brillet G et al; Invest Radiol 29 (3): 352-4 (1994)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ Whatever the species or the salt used, Gd-DOTA appears safer in its acute toxicity than Gd-DTPA with an 85% higher safety factor. These results can be explained by the greater stability of Gd-DOTA (very slow kinetics of dissociation and greater specificity of DOTA than DTPA for gadolinium), and the lower osmolality of DOTA than DTPA. ... /Gadoterate meglumine (gadolinium DOTA) and gadolinium DTPA/
[Allard M et al; Invest Radiol 23 Suppl 1:S271-4 (1988)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the liver from a number of toxicants that require biotransformation to elicit toxicity (i.e. 1,2-dichlorobenzene and CCl4), as well as compounds that do not (i.e. cadmium chloride and beryllium sulfate). The mechanism of this protection is thought to result from reduced secretion of inflammatory and cytotoxic products from Kupffer cells (KC). However, since other lanthanides have been shown to decrease cytochrome P450 (P450) activity ... male and female Sprague-Dawley rats were given GdCl3 (iv, 10 mg/kg). Twenty-four hours later, livers were either processed for preparation of microsomes or for primary cultures of hepatocytes. Gadolinium chloride treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by approximately 30% in males and 20% in females. In hepatocytes isolated from rats pretreated with GdCl3, the toxicity caused by CCl4, but not CdCl2 was reduced. ... /Gadolinium chloride/
[Badger DA et al; Toxicology 121 (2): 143-53 (1997)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ Kinetics of gadolinium accumulation was studied by inductively coupled plasma-emission spectroscopy after intravenous injection of this agent (7.5 mg/kg) to CBA mice. Gadolinium exhibits lysosomotropic properties (long-term selective accumulation in lysosomes in vivo). Gadolinium uptake by hepatic cells attained maximum 1 hr after its intravenous injection and remained at this level during the next day. Accumulation of gadolinium in hepatocytic lysosomes disturbed their osmotic properties (as was seen from the increase in free acid phosphatase activity, which persisted for 19 days). Serum activities of beta-D-galactosidase and beta-D-glucuronidase also increased (24 to 72 hr and day 19). Selective depression of liver macrophages (24 to 48 hr) was accompanied by a decrease in serum chitotriosidase activity. We conclude that accumulation of gadolinium in lysosomes of liver macrophages leads to their damage and elimination of a certain population of macrophages (primarily large cells). Changes in activity of serum lysosomal enzymes also reflect repopulation of liver macrophages. /Gadolinium/
[Korolenko TA et al; Bull Exp Biol Med 142 (4): 391-4 (2006)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 + or - 0.17 ppm and 0.47 + or - 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 + or - 0.46 ppm for the bolus and 1.24 + or - 0.39 ppm for the bolus/constant infusion strategy and 0.16 + or - 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.
[Bartolini ME et al; Magn Reson Imaging 21 (5): 541-4 (2003)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Acute Exposure/ The aim of this study was to characterize rat Kupffer cell TNFalpha production, phagocytic function, and ED1 /(SRP: ED1 antibody specific for exudate macrophages)/ and ED2 /(SRP: ED2 antibody recognizing cell membrane antigens of resident macrophages, including Kupffer cells)/ antigen expression following the administration of gadolinium chloride (GdCl3). For in vivo experiments, rats received 10 mg/kg GdCl3 iv or sterile saline. Lipopolysaccharide 3 mg/kg ip (LPS) was administered 4 hr prior to sacrifice on Days 1 to 3, 5 or 8 following GdCl3 injection. Hepatic ED1 and ED2 positive macrophage numbers and TNFalpha mRNA levels were determined. ... In vivo, the proportion of ED1 positive cells which were ED2 positive was reduced from 87 to 3% and hepatic TNFalpha mRNA levels following LPS declined by 60% over Days 1 to 5 after injection of GdCl (P<0.01). /It was concluded/ that GdCl3 significantly reduces ED2 expression by Kupffer cells in vivo. ... /Gadolinium chloride/
[Lee CM et al; Int J Biochem Cell Biol 36 (3): 481-8 (2004)] **PEER REVIEWED** PubMed Abstract

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats with gadopentetate dimeglumine at doses 2.5 times, and in rabbits at doses 7.5 and 12.5 times, the human dose have shown that this agent causes slight retardation in development. /Gadopentetate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats showed that gadoteridol at doses 33 times the maximum recommended human dose for 12 days during gestation doubled the incidence of postimplantation loss. Also, when rats were administered gadoteridol at doses 20 to 33 times the maximum human dose for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. /Gadoteridol/
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/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Offspring of female rats given 4.9 mmol/kg (10 times the human dose based on BSA) daily on days 7 through 17 of gestation exhibited reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development. Maternal toxicity was also observed at this dose. Doses of 0.7 mmol per kg daily did not produce these effects. Studies in rabbits given 0.4 or 1.6 mmol per kg daily (1 and 4 times the human dose, respectively, based on BSA) revealed fetuses with forelimb flexures and cardiovascular abnormalities, including malformed arteries, septal defects, and abnormal ventricular structure. Doses of 0.1 mmol per kg daily (0.3 times the human dose based on BSA) did not produce these defects. Maternal toxicity was not observed at any dose. /Gadoversetamide/
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/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Gadoversetamide had a negative impact on male rat fertility, causing reduction and degeneration of spermatocytes, when given intravenously at doses of 2 mmol per kg (four times the human dose based on body surface area [BSA]) for seven weeks. These effects were not seen at doses of 0.5 mmol per kg (one time the human dose based on BSA). Reduction of male rat reproductive organ weight, testicular germinal epithelium degeneration, germ cell presence in epididymides, and reduced sperm count were all seen at intravenous doses of 3 mmol per kg daily (six times the human dose based on BSA) given for 28 days. These effects were not observed at a dose of 0.6 mmol per kg (one time the human dose based on BSA), nor were these effects observed in studies performed on dogs. One-time 0.5 to 15 mmol per kg (1 to 25 times the human dose based on BSA) doses did not produce adverse effects on the reproductive system in male rats. /Gadoversetamide/
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/ALTERNATIVE and IN VITRO TESTS/ For in vitro experiments, /rat/ Kupffer cells were cultured in the presence of 0 to 270 uM gadolinium chloride (GdCl3) for 24 hr following which viability, TNFalpha protein production in response to lipopolysaccharide (LPS) (10 ng/mL), phagocytosis, and ED1 and ED2 /(SRP: ED1 antibody specific for exudate macrophages; ED2 antibody recognizing cell membrane antigens of resident macrophages, including Kupffer cells)/ staining were evaluated. ... In vitro, phagocytosis declined with increasing concentrations of GdCl3. GdCl3 (0 to 27 uM) did not affect cultured Kupffer cell viability, TNFalpha production, ED1 or ED2 staining. ... In vitro, GdCl3 /had/ a dose dependent effect on phagocytosis but only /affected/ viability and TNFalpha production at high concentrations. ED2 expression of cultured Kupffer cells is not affected by GdCl3.
[Lee CM et al; Int J Biochem Cell Biol 36 (3): 481-8 (2004)] **PEER REVIEWED** PubMed Abstract

/ALTERNATIVE and IN VITRO TESTS/ The effect of gadolinium chloride (GdCl3) on the content of rat liver mitochondrial cytochromes was investigated in relation to the basal rate of O2 uptake and Kupffer cell functioning, assessed in liver perfusion studies. (1) A single dose of GdCl3 (10 mg/kg) produced a significant diminution in Kupffer cell functioning, evidenced by the decreases in colloidal carbon uptake and in carbon-induced O2 uptake observed at 6-24 hr after treatment, without changes in the sinusoidal lactate dehydrogenase efflux as index of tissue viability; at 48 hr after GdCl3 administration, carbon phagocytosis was recovered to control values, whereas carbon-induced O2 uptake remained lower than control values. (2) GdCl3 also caused a 34% decrease in the basal rate of O2 consumption of the liver at 24 hr after treatment, which returned towards control values at 48 hr. (3) The content of mitochondrial cytochromes c1 and c at 24 h after GdCl3 treatment was significantly reduced by 40 and 32%, respectively, which returned to control values at 48 h, without changes in that of cytochromes b and a+a3. It is concluded that GdCl3-induced decrease in liver O2 consumption is a reversible phenomenon that seems to be due to a diminution in the content of mitochondrial cytochromes c1 and c. /Gadolinium chloride/
[Ferreira J et al; FEBS Lett 426 (2): 263-5 (1998)] **PEER REVIEWED** PubMed Abstract

/ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to examine the effect of GdCl3 inhibition of Kupffer cells activation on lipid peroxidation after severe total hepatic ischemia/reperfusion. ... Wistar rats (n = 40) were randomly divided into a sham-operation group, a control ischemia/reperfusion group, and two ischemia/reperfusion groups pretreated with GdCl3 (10 mg and 20 mg/kg bw iv, 48 and 24 hr prior to operation). Following 60 min of total hepatic ischemia and 120 min of reperfusion, the rats were sacrificed, and liver samples were taken for determination of malondialdehyde and light microscopy examination. Blood samples were also taken for assay of aspartate and alanine transaminase. Additional animals (n = 60) were followed up for a 7-day survival rate determination. ... Ischemia/reperfusion decreased the survival rate to 13.3%, increased (p < 0.001) the levels of aspartate and alanine transaminase in serum to 2387 + or - 75 and 2157 + or - 87 IU/L, respectively, and increased (p < 0.001) malondialdehyde levels in liver to 1.609 + or - 0.096 nmol/g compared with 1.164 + or - 0.060 in the sham operation group. Pretreatment with GdCl3 increased the survival rate to 60%, and decreased (p < 0.001) the levels of aspartate transaminase in serum to 1549 + or - 66 and 1496 + or - 55 IU/L, the levels of alanine transaminase in serum to 1302 + or - 48 and 1305 + or - 63 IU/L, and the levels of malondialdehyde in liver to 1.132 + or - 0.034 and 1.149 + or - 0.57 nmol/g for the lower and the higher doses of GdCl3, respectively. Histological examination showed protection of liver parenchyma in the animals treated with GdCl3. ... /Gadolinium chloride/
[Giakoustidis DE et al; Hepatogastroenterology 50 (53): 1587-92 (2003)] **PEER REVIEWED** PubMed Abstract

/GENOTOXICITY/ Gadoversetamide was not found to be mutagenic in the Ames assay, mouse lymphoma mutagenesis assay, or mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive. /Gadoversetamide/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**


Metabolism/Pharmacokinetics:


Absorption, Distribution & Excretion:
Elimination: Urine: 78% to 96%. Feces: 0.6% to 4%. /Gadobenate dimeglumine/
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Studies in rats have shown that less than 0.5% of the administered dose is transferred from the mothers' milk to neonates. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Rapidly cleared from blood after intravenous administration and distributed in extracellular space. /Gadopentetate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Elimination: Renal, by passive filtration (approximately 83% of dose excreted within 6 hours). /Gadopentetate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Elimination: Renal (approximately 94% of dose excreted within 24 hours). /Gadoteridol/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Kinetics of gadolinium accumulation was studied by inductively coupled plasma-emission spectroscopy after intravenous injection of this agent (7.5 mg/kg) to CBA mice. Gadolinium exhibits lysosomotropic properties (long-term selective accumulation in lysosomes in vivo). Gadolinium uptake by hepatic cells attained maximum 1 hr after its intravenous injection and remained at this level during the next day. Accumulation of gadolinium in hepatocytic lysosomes disturbed their osmotic properties (as was seen from the increase in free acid phosphatase activity, which persisted for 19 days). Serum activities of beta-D-galactosidase and beta-D-glucuronidase also increased (24 to 72 hr and day 19). Selective depression of liver macrophages (24 to 48 hr) was accompanied by a decrease in serum chitotriosidase activity. We conclude that accumulation of gadolinium in lysosomes of liver macrophages leads to their damage and elimination of a certain population of macrophages (primarily large cells). Changes in activity of serum lysosomal enzymes also reflect repopulation of liver macrophages. /Gadolinium/
[Korolenko TA et al; Bull Exp Biol Med 142 (4): 391-4 (2006)] **PEER REVIEWED** PubMed Abstract

Pharmacokinetic and acute-toxicity studies of Gd-DOTA meglumine (Mgl) were evaluated in various animals and compared with those of Gd-DTPA Mgl. The agents were injected intravenously at two dosages: 0.1 or 0.5 mmol/kg. Various organs and tissues were removed at specified times after injection and assayed for gadolinium (Gd) concentration. The two complexes behave in an identical fashion in their short-term biodistribution and excretion. The very rapid distribution in the body (except in the brain) and the high clearance from blood are due to an extravascular distribution. The small distribution volume and the very high hydrophilicity account for its extracellular localization. There is no accumulation within any organ. Rapid disappearance, short half-life, size, and hydrophilicity of these molecules are in agreement with urinary elimination by free glomerular filtration. ... /Gadoterate meglumine (gadolinium DOTA) and gadolinium DTPA/
[Allard M et al; Invest Radiol 23 Suppl 1: S271-4 (1988)] **PEER REVIEWED** PubMed Abstract

Elimination: Renal, by glomerular filtration (approximately 96% of dose excreted within 24 hours). Slightly delayed in patients with renal insufficiency. /Gadoversetamide/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 + or - 0.17 ppm and 0.47 + or - 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 + or - 0.46 ppm for the bolus and 1.24 + or - 0.39 ppm for the bolus/constant infusion strategy and 0.16 + or - 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.
[Bartolini ME et al; Magn Reson Imaging 21 (5): 541-4 (2003)] **PEER REVIEWED** PubMed Abstract

In vivo gadolinium release was evaluated for MultiHance, Omniscan and Gadovist estimating gadolinium content in liver, kidneys, spleen, femur and brain after single or repeated intravenous administrations to rats at 1 mmol/kg. Gadolinium acetate (GdAc) at a daily dose of 0.03 mmol/kg and physiological saline were used as positive and negative controls, respectively. No changes in blood chemistry, hematology nor histopathology were seen with any of the tested contrast media, whereas an increase in white blood cell count and in serum cholesterol were found after GdAc at 0.18 mmol/kg cumulative dose. Analogously, gadolinium content in target organs (as % of injected dose) after any of contrast media was 100-200 times lower than after GdAc, either after single or repeated administrations. Under these experimental conditions, the rank of residual gadolinium found in these organs was GdAcOmniscan >Gadovist >MultiHance. Depopulation of lymphocytes in periarteriolar lymphatic sheaths (PALS) areas of the spleen was noted in rats treated with a single dose of GdAc sacrificed 24 hr post-dosing, but not in repeated dose rats sacrificed 48 hr after last dosing. It was, therefore, concluded that this was a transient phenomenon and that PALS are rapidly repopulated with lymphocytes. With all contrast media, gadolinium content after a 2-day washout following a 3-week repeated administration period was lower than the amount found 24 hr after a single administration. Accordingly, the observed gadolinium content in organs should actually be in a complexed form (possibly the injected complex) which is subjected to elimination. /Gadolinium acetate/
[Bussi S et al; Exp Toxicol Pathol 58 (5): 323-30 (2007)] **PEER REVIEWED** PubMed Abstract


Biological Half-Life:
Distribution: 3.7+ or - 2.7 minutes (mean). Elimination: 77.8 + or - 16 minutes (mean). /Gadodiamide/
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Distribution: 0.084 + or - 0.012 to 0.0605 + or - 0.072 hours. Elimination: 1.17 + or - 0.26 to 2.02 + or - 0.60 hours. Elimination: 6.1 + or -3.0 to 9.5 + or - 3.1 hours for moderate and severe renal impairment. Elimination: 1.2 + or - 0.29 hours for patients with end-stage renal disease on dialysis compared to 42.4 + or - 24.4 hours when off dialysis. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Elimination: 1.6 + or - 0.13 hours (mean). /Gadopentetate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Distribution: 0.20 + or - 0.04 hours (mean). Elimination: 1.57 + or - 0.08 hours (mean). /Gadoteridol/
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Distribution: 13.3 + or - 6.8 (mean) minutes. Elimination: 103.6 + or - 19.5 (mean) minutes. /Gadoversetamide/
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Interactions:
Macrophages infiltrating injured tissue play an important part in fibrogenesis. To shed light on the functional roles of macrophages, ... the appearance of macrophage populations in thioacetamide (TAA)-induced rat hepatic lesions /was investigated/, with or without pretreatment with GdCl(3), a chemical capable of inhibiting Kupffer cell functions. In the GdCl(3)+TAA group rats received a single ip injection of GdCl(3) (7.5mg/kg body weight) and, after 24 hr, a single intravenous injection of TAA (300 mg/kg body weight). Rats in the TAA group received TAA only. Rats in both groups were examined on post-TAA injection (PTI) days 3, 5, and 7. In the TAA group, on PTI day 3, when TAA-induced hepatocyte injury was particularly prominent, the number of macrophages peaked, subsequently decreasing until PTI day 7. As compared with the TAA group, the GdCl(3)+TAA group showed significantly decreased numbers of ED1-immunolabelled cells (exudate macrophages) and ED2-immunolabelled cells (Kupffer cells) on PTI days 3, 5, and 7, and OX6-immunolabelled cells (antigen-presenting macrophages) on PTI days 3 and 5. Although less strikingly, the numbers of alpha-smooth muscle actin-positive myofibroblasts and fibrotic areas were decreased in the GdCl(3)+TAA group. By RT-PCR, the expression of TGF-beta1 mRNA was suppressed on PTI days 3 and 7 in the GdCl(3)+TAA group, and the suppressed expression was confirmed in vitro by treating rat macrophage-like cells (HS-P) with 1% GdCl(3). The study showed that GdCl(3) treatment decreased the numbers of macrophages appearing in hepatic lesions and inhibited TGF-beta1 mRNA expression in macrophages. Decreased numbers of macrophages may contribute to improvement of hepatic fibrosis. /Gadolinium chloride/
[Ide M et al; J Comp Pathol 133 (2-3): 92-102 (2005)] **PEER REVIEWED** PubMed Abstract

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1 mmol/kg), were intraperitoneally injected with thioacetamide (6.6 mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96 hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNF alpha and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. /It was concluded/ that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. ... /Gadolinium chloride/
[Andres D et al; Biochem Pharmacol 66 (6): 917-26 (2003)] **PEER REVIEWED** PubMed Abstract

Gadolinium chloride (GdCl3) reportedly inhibits Kupffer cell function including TNF-alpha production and thereby improves organ dysfunctions after lipopolysaccharide (LPS) challenge, particularly in partially hepatectomized (PH) mice. In addition, TNF-alpha reportedly promotes the regeneration of hepatocytes after PH. However, /the authors/ have frequently seen GdCl3 treatment increase the mortality of normal mice after LPS injection. ... The mice treated by GdCl3 (10 mg/kg, iv) at 24 hr before LPS challenge showed increased serum TNF-alpha and ALT levels after LPS challenge and a decreased mouse survival rate. The Kupffer cells from GdCl3-treated mice consistently produced a much larger amount of TNF-alpha following in vitro LPS stimulation than those of the control mice despite the fact that the Kupffer cells decreased in number and also demonstrated decreased superoxide production. Anti-TNF-alpha Ab before LPS-injection greatly improved GdCl3-induced mouse mortality and the degree of liver injury. In marked contrast, the increased amount of TNF-alpha induced by GdCl3 improved the survival after LPS challenge in PH mice because TNF-alpha promoted hepatocyte mitosis/regeneration in PH liver as evidenced by the fact that the inhibition of TNF-alpha before PH suppressed hepatocyte regeneration and decreased survival after LPS challenge. In conclusion, GdCl3 depletes the superoxide-producing Kupffer cells but conversely enhances the function of TNF-alpha-producing Kupffer cells, which thereby leads to LPS-induced mortality. Meanwhile, the increased TNF-alpha production induced by GdCl3 supports liver regeneration and increases the survival after LPS challenge in PH mice.
[Kinoshita M et al; Shock 23 (1): 65-72 (2005)] **PEER REVIEWED** PubMed Abstract

... This article evaluates the role of Kupffer cells on cycloheximide (CHX)-induced hepatic injury using gadolinium chloride (GdCl(3)) for the inhibition of Kupffer cells. One group of rats was treated with CHX (CHX group), and another was treated with GdCl(3) before being treated with the same dose of CHX (GdCl(3)/CHX group). The necrotic change in the GdCl(3)/CHX group was exacerbated under the induction of hepatocellular apoptosis by the CHX treatment. A substantial diminution of the number of ED1- or ED2-positive cells /(SRP: ED1 antibody specific for exudate macrophages; ED2 antibody recognizing cell membrane antigens of resident macrophages, including Kupffer cells)/ was demonstrated in the GdCl(3)/CHX group compared to the CHX group. In addition, the degree of decrease in ED2-positive cells was more apparent than that in ED1-positive cells. Increases in the mRNA levels of IL-10 and Stat3 were observed in the CHX group, but not in the GdCl(3)/CHX group. On the other hand, the hepatic mRNA levels of chemokines and adhesion molecules such as Ccl20, LOX-1, and E-selectin were significantly increased only in the GdCl(3)/CHX group. Thus, Kupffer cell inactivation by the GdCl(3) treatment leads to a loss of the capacity to produce IL-10, supposedly resulting in the enhancement of pro-inflammatory cytokine activities such as tumor necrosis factor (TNF) signaling. These events are suggested to be a factor of the inflammatory exacerbation in the livers of the GdCl(3)/CHX group. ... /Gadolinium chloride/
[Kumagai K et al; Toxicology 241(3):106-18 (2007)] **PEER REVIEWED** PubMed Abstract

The aim of this study was to investigate whether matrix metalloproteinases (MMP-13, 9) of Kupffer cells induced by gadolinium chloride (GdCl(3)) treatment can reverse dimethylnitrosamine (DMN)-induced liver fibrosis (in vivo) and the effect of GdCl(3) on MAP kinase activity (in vitro). Male Wistar rats 6 weeks of age received DMN (10 mg/kg) three successive days a week for 4 weeks. Then two groups of rats (n = 6 each) were treated twice weekly with either GdCl(3) (7 mg/kg) or saline solution intravenously for the next 4 weeks. Animals were sacrificed to estimate the degree of liver fibrosis. Isolated Kuppfer cells were treated with GdCl(3) and the expressions of MMPs, MAP kinase activity (ERK, SAPK/JNK, P38) as well as apoptosis were also examined. Rats that received DMN for 4 weeks followed by GdCl(3) injection for 4 weeks showed an reduced liver hydroxyproline content compared to rats treated with DEN followed by saline (277 +/- 22 VS 348 +/- 34 ug/g, n = 6 each, P < 0.01). There were significantly increased MMP-13 mRNA levels in GdCl(3)-treated rats. However, no significant change was observed in procollagen type I mRNA levels. Isolated Kuppfer cells treated with GdCl(3) showed increased MAP kinase activity, especially P38 pathway as well as MMP-13, 9 mRNA and type I collagen-degrading activity leading to apoptosis. SB203580, inhibitor of P38 pathway diminished these activations and prevented apoptosis. These results suggest that Kuppfer cells can reverse liver fibrosis via the expression of MMPs mainly through P38 pathway. /Gadolinium chloride/
[Sakaida I et al; Life Sci 72 (8): 943-59 (2003)] **PEER REVIEWED** PubMed Abstract

The role of Kupffer cells in the hepatocellular injury and oxidative stress induced by lindane (20 mg/kg; 24 hr) in hyperthyroid rats (daily doses of 0.1 mg L-3,3',5-triiodothyronine (T3)/kg for three consecutive days) was assessed by the simultaneous administration of gadolinium chloride (GdCl3; 2 doses of 10 mg/kg on alternate days). Hyperthyroid animals treated with lindane exhibit enhanced liver microsomal superoxide radical (O2.-) production and NADPH cytochrome c reductase activity, with lower levels of cytochrome P450, superoxide dismutase (SOD) and catalase activity, and glutathione (GSH) content over control values. These changes are paralleled by a substantial increase in the lipid peroxidation potential of the liver and in the O2.- generation/ SOD activity ratio, thus evidencing a higher oxidative stress status that correlates with the development of liver injury characterized by neutrophil infiltration and necrosis. Kupffer cell inactivation by GdCl3 suppresses liver injury in lindane/T3-treated rats with normalization of altered oxidative stress-related parameters, excepting the reduction in the content of GSH and in catalase activity. ... /Gadolinium chloride/
[Simon-Giavarotti KA et al; Free Radic Res 36 (10): 1033-9 (2002)] **PEER REVIEWED** PubMed Abstract

... This study was conducted to determine whether gadolinium chloride (GdCl3) prevents Cd-induced hepatotoxicity via the induction of metallothionein (MT). Hepatic MT and Kupffer cell counts were analyzed 24 hr after wild-type (WT) mice were administered saline or 10, 30, or 60 mg GdCl3/kg. GdCl3 induced MT in a dose-dependent manner without affecting nonprotein sulfhydryl content. All examined doses of GdCl3 were effective at eliminating Kupffer cells from the liver. To examine the hepatoprotective effects of GdCl3, WT and MT-null mice were pretreated with saline or 10, 30, or 60 mg GdCl3 24 hr prior to a hepatotoxic dose of Cd (2.5 mg Cd/kg). Blood and livers were removed 16 hr later and analyzed for hepatotoxicity as well as MT, Cd, and Kupffer cell content. Hepatotoxicity was alleviated in both WT and MT-null mice that were pretreated with 30 or 60 mg GdCl3/kg, indicating that MT induction is not required for the hepatoprotective effects of GdCl3. Hepatic Cd content was not decreased by GdCl3, demonstrating that GdCl3 does not negatively affect Cd distribution to the liver. Kupffer cells were depleted at all three doses of GdCl3, whereas hepatoprotection was only observed at doses of 30 and 60 mg GdCl3/kg. This does not rule out Kupffer cells in the mechanism of Cd-induced hepatotoxicity, but it does suggest that GdCl3 exerts hepatoprotective effects on the liver aside from depleting Kupffer cells. In summary, these data substantially rule out MT induction and decrease the importance of Kupffer cells as mechanisms of GdCl3-induced protection from Cd-induced hepatotoxicity. /Gadolinium chloride/
[Harstad EB, Klaassen CD; Toxicol Appl Pharmacol 180 (3): 178-85 (2002)] **PEER REVIEWED** PubMed Abstract

... The objective of these studies was to determine the involvement of Kupffer cells in cadmium induced liver injury by inhibiting their function with gadolinium chloride (GdCl3). Male Sprague-Dawley rats were administered GdCl3 (10 mg/kg, iv) followed 24 hr later by a single dose of CdCl2 (3.0 and 4.0 mg/kg, iv). Twenty four hours after CdCl2 administration animals were killed and the degree of liver toxicity was assessed using plasma alanine aminotransferase (ALT), as well as light microscopy. Cadmium chloride administration produced multifocal hepatocellular necrosis and increased plasma ALT activity. Pretreatment with GdCl3 significantly reduced both the morphological changes and hepatic ALT release caused by CdCl2. However, the protection was specific to the liver, and did not alter CdCl2 induced testicular injury, as determined by histopathological damage. ... /Gadolinium chloride/
[Sauer JM et al; Toxicology 121 (2): 155-64 (1997)] **PEER REVIEWED** PubMed Abstract

Modifications of hepatocyte cell surface were determined after single iv injection to rats of Pb(NO(3))(2) (known to induce liver hyperplasia followed by apoptosis) or GdCl(3) (known to induce proliferation of parenchymal cells and Kupffer cell depletion) or administration of GdCl(3) 24 hr before Pb(NO(3))(2) injection (known to reduce hyperplasia and apoptosis induced in the parenchymal liver cells by the single Pb(NO(3))(2) injection). Rats were sacrificed at fixed times after the treatments (1, 3 and 5 days) and hepatocytes were isolated by enzymatic liver perfusion. In spite of the intracellular target of the heavy metals, signals leading to liver hyperplasia and apoptosis (with rates different for the different experimental conditions) were generated, which in turn were responsible for cell surface alteration. Increment or decrement of phosphatidylserine (PS) expression, asialoglycoprotein receptors (ASGPRs) and sugar residue expression on hepatocyte surfaces was measured in parallel with apoptosis and proliferation. When GdCl(3) was injected 24 hr before Pb(NO(3))(2) injection, liver modifications were significantly reduced, thus suggesting that GdCl(3) could prevent and/or reduce liver damage. /Gadolinium chloride/
[Pagliara P et al; Cell Tissue Res 312 (1): 41-8 (2003)] **PEER REVIEWED** PubMed Abstract

Newborn rats exposed to 60% O(2) for 14 days demonstrated a bronchopulmonary dysplasia-like lung morphology and pulmonary hypertension. .... To determine whether macrophage accumulation played an essential role in the development of pulmonary hypertension in this model, pups were treated with gadolinium chloride (GdCl(3)) to reduce lung macrophage content. Treatment of 60% O(2)-exposed animals with GdCl(3) prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphologic changes in the lung parenchyma. In addition, GdCl(3) inhibited 60% O(2)-mediated increases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. ... /Gadolinium chloride/
[Jankov RP et al; Pediatr Res 50 (2): 172-83 (2001)] **PEER REVIEWED** PubMed Abstract

... To elucidate the role of Kupffer cells in liver fibrosis and cirrhosis, rats were treated with gadolinium chloride (GdCl(3)) and cirrhosis was induced by subchronic carbon tetrachoride (CCl(4)) administration. Carbon tetrachloride was administered three times per week for 8 weeks to male Wistar rats treated simultaneously with GdCl(3) (20 mg/kg, ip daily); appropriate controls were performed. Serum enzyme activities of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (gamma-GTP) and alanine aminotransferase (ALT) and bilirubin concentration increased significantly by CCl(4), whereas GdCl(3) prevented completely the increase in gamma-GTP and partially prevented the increase in ALP, ALT and bilirubins (P < 0.05). Liver glycogen was depleted by CCl(4), an effect that GdCl(3) was not capable of preventing. Moreover, gadolinium by itself depleted it. Lipid peroxidation increased about 2.5-fold by administration with CCl(4), whereas GdCl(3) preserved lipid peroxidation within normal values. Hepatic collagen increased threefold after subchronic intoxication with CCl(4) (P < 0.05) whereas GdCl(3) prevented partially (P < 0.05) the increase in collagen content, as evidenced by the liver hydroxyproline content and by the histopathological analysis. ... /Gadolinium chloride/
[Muriel P, Escobar Y; J Appl Toxicol 23 (2): 103-8 (2003)] **PEER REVIEWED** PubMed Abstract

...The present study ... investigated the effects of Kupffer cell depletion by gadolinium on fumonisin B1(FB1) hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 hr later they were treated with sc injections of vehicle or 2.25 mg/kg/day FB1 in saline for three successive days. Gadolinium significantly attenuated FB1-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB1-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB1 treatments individually increased the expression of selected cell signal factors; e.g., TNFalpha, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin beta, interferon gamma, and transforming growth factor beta1; gadolinium chloride did not alter FB1-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB1 hepatotoxicity. Decreased FB1-induced sphinganine accumulation and increased protective TNFalpha signaling by gadolinium chloride may in part account for its ameliorating effect on FB1 liver damage. /Gadolinium chloride/
[He Q et al; Toxicology 207 (1): 137-47 (2005)] **PEER REVIEWED** PubMed Abstract

The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the liver from a number of toxicants that require biotransformation to elicit toxicity (ie 1,2-dichlorobenzene and CCl4), as well as compounds that do not (ie cadmium chloride and beryllium sulfate). The mechanism of this protection is thought to result from reduced secretion of inflammatory and cytotoxic products from Kupffer cells (KC). However, since other lanthanides have been shown to decrease cytochrome P450 (P450) activity ... male and female Sprague-Dawley rats were given GdCl3 (iv, 10 mg/kg). Twenty-four hours later, livers were either processed for preparation of microsomes or for primary cultures of hepatocytes. Gadolinium chloride treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by approximately 30% in males and 20% in females. In hepatocytes isolated from rats pretreated with GdCl3, the toxicity caused by CCl4, but not CdCl2 was reduced. ... /Gadolinium chloride/
[Badger DA et al; Toxicology 121 (2): 143-53 (1997)] **PEER REVIEWED** PubMed Abstract


Pharmacology:


Therapeutic Uses:
Gadodiamide is indicated to provide contrast enhancement during MRI and thus facilitate visualization of lesions in the spine and associated tissues. /Gadodiamide; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadodiamide is indicated to provide contrast enhancement during magnetic resonance imaging (MRI) and thus facilitate visualization of intracranial lesions with abnormal vascularity or those suspected of causing an abnormality in the blood-brain barrier. /Gadodiamide; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadobenate is indicated for intravenous use in magnetic resonance imaging (MRI) of the CNS in adults to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine and associated tissues. /Gadobenate; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

MRI with gadopentetate dimeglumine is particularly useful in patients with normal unenhanced studies who have central nervous system (CNS) symptoms, in patients with CNS tumors that are difficult to separate from surrounding edema, and in patients who have undergone surgery, to differentiate recurrence of the lesions from postoperative changes. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

MRI with gadopentetate dimeglumine may be useful in differentiating postoperative epidural fibrosis (scar tissue) from recurrent disk herniation in patients with symptoms of failed back surgery syndrome, to avoid unnecessary, and possibly damaging, reoperation if scar tissue is the cause. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

MRI of the breast is also used in patients with postoperative scarring and silicon implants to exclude or demonstrate malignancy, especially in patients with uncertain mammographic and/or clinical findings. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate dimeglumine is indicated in adults to improve lesion contrast duringMRbody imaging (excluding the heart) in the evaluation of suspected hepatic lesions, endometrial or cervical carcinomas or pelvic masses, breast lesions (suspected or known), and musculoskeletal lesions. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate-enhanced MRI is used in the evaluation of patients with great vessel disease (e.g., aortic aneurysm, aortic dissection, congenital abnormalities, vena cava obstruction); in patients with ischemic cardiac disease to examine the heart for regions of wall thinning and intracardiac thrombus, to assess chamber size, myocardial mass, wall motion, and wall thickening, and to detect regions of acute infarction; and in patients with congenital heart disease to evaluate malrotations of the heart and for postsurgery assessment. Also, gadopentetate-enhanced MRI helps in the assessment of coronary artery reperfusion after thrombolysis. /Gadopentetate dimeglumine; NOT included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate dimeglumine provides enhanced contrast of epidural abscesses, which makes it possible to differentiate them from adjacent compressed thecal sac; it facilitates the diagnosis of disk space infection and osteomyelitis; it helps localize portions of paraspinal masses most likely to yield a positive percutaneous biopsy; and it helps distinguish active spinal infections from those that have responded adequately to antibiotic therapy. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate dimeglumine is indicated in adults and children 2 years of age and older to provide contrast enhancement and facilitate visualization of lesions in the spine and associated tissues. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

In patients with suspected meningitis, gadopentetate-enhanced MRI may be particularly useful in defining the active inflammatory process of the meninges and focal lesions. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate dimeglumine is used in magnetic resonance (MR) studies to help differentiate changes that ur secondary to brain tumor resection (e.g., encephalomalacia, gliosis) or to postoperative irradiation or chemotherapy (e.g., edema, ischemia, demyelination, necrosis) from changes that represent residual or recurrent tumors, to accurately assess treatment results. /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadopentetate dimeglumine is indicated in adults and children 2 years of age and older to provide contrast enhancement during magnetic resonance imaging (MRI) of intracranial lesions with abnormal vascularity or those suspected of causing an abnormality in the blood-brain barrier. Gadopentetate-enhanced MRI helps in the diagnosis and characterization of neoplastic disease, acoustic neuroma, subacute infarction, inflammatory disease, certain vascular abnormalities, and certain demyelinating abnormalities (e.g., multiple sclerosis). /Gadopentetate dimeglumine; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadoteridol is indicated to provide contrast enhancement during MRI and facilitate visualization of lesions in the spine and associated tissues. /Gadoteridol; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadoteridol is indicated to provide contrast enhancement during magnetic resonance imaging (MRI) and facilitate visualization of intracranial lesions with abnormal vascularity or those suspected of causing an abnormality in the blood-brain barrier. /Gadoteridol; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadoversetamide is indicated in adults to provide contrast enhancement and thus to facilitate visualization during MRI of lesions in the liver with abnormal vascularization in patients who are suspected on computed tomography of having structural abnormalities. /Gadoversetamide; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadoversetamide is indicated in adults to provide contrast enhancement during MRI of lesions of the spine and associated tissues. /Gadoversetamide; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Gadoversetamide is indicated in adults to provide contrast enhancement during magnetic resonance imaging (MRI) and thus to facilitate visualization of intracranial lesions in patients with an abnormal blood brain barrier or abnormal vascularity of the brain. /Gadoversetamide; Included in US product labeling/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

/VET/ Gadolinium complexes are not considered to be a drug class at high risk for prolonging cardiac repolarization, which can lead to potentially life-threatening arrhythmias such as torsade de pointes. However, only limited robust data are available on these compounds despite their extensive use as contrast enhancers in magnetic resonance imaging. ... An overview of recent cardiovascular safety data obtained on gadoterate meglumine (Gd-DOTA) /is presented/. ... Cardiovascular safety was evaluated by state-of-the-art nonclinical ex vitro (dog Purkinje fibers) and in vivo studies in both normal (dogs) and sensitized animal models (rabbits) and in patients with various diseases in a specific clinical trial. ... In all of these studies, Gd-DOTA did not show any direct deleterious effect on cardiac electrophysiology and especially on ventricular repolarization. ... These results confirmed the good safety profile of Gd-DOTA derived from postmarketing evaluations. Nonspecific gadolinium complexes used for magnetic resonance contrast enhancement do not constitute a class-at-risk for drug-related arrhythmias. /Gadoterate meglumine/
[Bourrinet P et al; Invest Radiol 42 (2): 63-77 (2007)] **PEER REVIEWED** PubMed Abstract

/EXPL THER/ Vasovist ... is a newly developed blood pool contrast agent for magnetic resonance imaging with a high affinity for human albumin, making it an ideal tool for the detection of structural abnormalities such as stenosis and aneurysm. For the risk assessment of the single diagnostic use in patients, the toxicity of this compound was investigated. ... Studies of acute, repeated-dose, reproductive, and developmental toxicity as well as local tolerance, immunotoxicity, and mutagenic potential were performed. ... Lethality was observed in rodents after single intravenous administration at doses of at least 2 orders of magnitude higher than the anticipated human dose of 0.03 mmol/kg. The no observed adverse effect level after repeated daily administration over the course of 4 weeks to monkeys exceeded the single diagnostic dose by a factor of 3.3. The main effect of repeated dosing in both rats and monkeys was vacuolation in kidney proximal tubules without concomitant effect on kidney function. Studies into reproduction toxicity have shown no evidence of effects on fertility or perinatal and postnatal development. Signs of embryo-fetal toxicity were observed in rabbits after repeated administration of high doses. No indications of immunotoxic and mutagenic effects were observed. In local tolerance testing, Vasovist was well tolerated after intravenous administration. ... Vasovist was well tolerated with reasonable safety margins between the single diagnostic dose of 0.03 mmol/kg in humans and the doses resulting in adverse effects in animal studies. /Vasovist/
[Steger-Hartmann T et al; Invest Radiol 41 (5): 449-59 (2006)] **PEER REVIEWED** PubMed Abstract

Magnetic resonance imaging (MRI) is based primarily on differences in proton density and proton relaxation dynamics. When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At the recommended dose, the effect is observed with greatest sensitivity in the T1-weighted sequences. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**


Drug Warnings:
Nephrogenic fibrosing dermopathy (NFD) causes thickening and hardening of the skin, often in the extremities, and urs in patients with underlying renal disease. The skin lesions can progress rapidly, sometimes leading to joint immobility and the inability to walk. In May 2006, nephrologists at hospital A in St. Louis, Missouri, reported to CDC and the Missouri Department of Health and Senior Services (MoDHSS) a cluster of NFD among patients treated in their dialysis units. CDC and MoDHSS conducted an investigation to determine the number of affected patients and identify risk factors for NFD. Thirty-three patients with NFD were identified in St. Louis, 28 of whom had been treated at hospital A. A matched case-control study was conducted at the hospital. This report summarizes the preliminary results of that study, which indicated that exposure to gadolinium-containing contrast agents during magnetic resonance imaging (MRI) studies was independently associated with NFD. Clinicians should be aware of the potential for NFD, and when possible, should avoid use of gadolinium-containing contrast agents in patients with advanced renal disease. /Gadolinium-containing contrast agents/
[Centers for Disease Control and Prevention (CDC); MMWR Morb Mortal Wkly Rep 56 (7): 137-41(2007)] **PEER REVIEWED** PubMed Abstract

It is not known to what extent that gadobenate dimeglumine is distributed into human milk. Breast-feeding should be discontinued prior to the administration of gadobenate and should not be restarted until at least 24 hours after the administration of gadobenate. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./ /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Studies indicate that gadoversetamide distributes into rat milk, however, it is unknown if this urs in humans. The manufacturer recommends discontinuing nursing and pumping and discarding breast milk for up to 72 hours after gadoversetamide administration. /Gadoversetamide/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./ /Gadodiamide; Gadopentetate dimeglumine; Gadoteridol; Gadoversetamide//
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007.] **PEER REVIEWED**

Adequate and well controlled studies in humans have not been done. Gadobenate should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. /Gadobenate dimeglumine/
[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1486] **PEER REVIEWED**

Gadolinium-based contrast media are important tools in diagnostic and interventional radiology that are particularly useful in patients with renal insufficiency. Recent reports in which exposure to gadolinium compounds has been linked to the development of nephrogenic systemic fibrosis in this patient population, however, are quite concerning. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, <60 mL/min/1.73 m(2)) to severe (glomerular filtration rate, <15 mL/min/1.73 m(2)) renal disease./Gadolinium-based contrast media/
[Chewning RH, Murphy KJ; J Vasc Interv Radiol 18 (3): 331-3 (2007)] **PEER REVIEWED** PubMed Abstract

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare fibrotic condition that presents in patients with a history of renal disease. The etiology is unknown, but it has recently been proposed that gadolinium, a paramagnetic contrast agent, may be a trigger of this disease. We report three patients with NSF with a history of use of gadolinium in magnetic resonance angiography a few weeks before the onset of symptoms. In the future, gadolinium should probably be avoided as much as possible in renal insufficiency patients until its role in the development of NSF is clarified. /Gadolinium contrast agents/
[Moreno-Romero JA et al; Br J Dermatol 157 (4): 783-7(2007)] **PEER REVIEWED** PubMed Abstract

... A case of serious adverse reaction following the administration of Gd-DTPA (gadolinium with diethylenetriamine pentaacetic acid) /is described/. The patient showed sneezing and hoarseness when Gd-DTPA was administered for the first time. At the second injection, when hydrocortisone was used in advance to prevent allergic reaction, she lapsed into a pre-shock state and anaphylactic reaction was strongly suggested by the laboratory data. The possibility that Gd-DTPA may cause the severe side effects must be noted. /Gadolinium DTPA/
[Nomura M et al; Nippon Igaku Hoshasen Gakkai Zasshi 53 (12): 1387-91 (1993)] **PEER REVIEWED** PubMed Abstract

... A case of anaphylactic shock due to gadoterate meglumine (DOTAREM) /is described/. While undergoing a magnetic resonance imaging examination, a 33-year-old nonatopic female patient became severely hypotensive, lost consciousness, and had generalized erythema immediately after the iv injection of this product. She recovered rapidly after she was given injection of epinephrine and her blood volume was restored with intravenous fluids. That DOTAREM had caused this immediate hypersensitivity reaction was proven by the positivity of prick-test and intradermal test at 10-3 (0.37 mg/mL) and in vitro leukocyte histamine release test. The results of these tests indicated that it was the gadoteric acid rather than the meglumine component of DOTAREM that was responsible: positivity of IDR at 10 mg/ml. Skin tests and leukocyte histamine release test to gadopentetate dimeglumine (MAGNEVIST) were negative. In addition of the exceptional character, this observation provides evidence for an immediate hypersensitivity without cross reactivity with gadopentetate dimeglumine. /Gadoterate meglumine/
[Beaudoin E et al; Allerg Immunol (Paris) 35 (10): 382-5 (2003)] **PEER REVIEWED** PubMed Abstract

... A case of acute renal failure after administration of gadolinium 0.09 mmol/kg body weight in a patient with preexisting mild renal failure (creatinine clearance 55 ml/min) is described. The additional renal damage was partially reversible. ... The reason for the preexisting renal failure was light-chain disease type kappa. This kind of renal damage may be especially susceptible to contrast media toxicity. /Gadolinium contrast agent/
[Jurgensen T et al; Med Klin (Munich) 102 (6): 480-2 (2007)] **PEER REVIEWED** PubMed Abstract

Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra-renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium-related contrast-induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF-gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium-chelate binding may expose tissues to toxic free Gd(3+) and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced chronic kidney disease or end-stage renal disease. /Gadolinium-containing contrast media/
[Perazella MA et al; Semin Dial 20 (3): 179-85 (2007)] **PEER REVIEWED** PubMed Abstract

A case of acute renal failure after administration of gadolinium 0.09 mmol/kg body weight in a patient with preexisting mild renal failure (creatinine clearance 55 mL/min) is described. The additional renal damage was partially reversible. ... The reason for the preexisting renal failure was light-chain disease type kappa. This kind of renal damage may be especially susceptible to contrast media toxicity. /Gadolinium-containing contrast media/
[Jurgensen T et al; Med Klin (Munich) 102 (6): 480-2 (2007)] **PEER REVIEWED** PubMed Abstract

Gadolinium is widely used as a magnetic resonance imaging contrast agent and is considered to have a good overall safety profile. Recently, both renal and extra-renal toxicities have been reported following exposure to gadolinium in patients with underlying kidney disease. Gadolinium-related contrast-induced nephropathy appears to be a risk in patients with advanced kidney disease and especially those with diabetic nephropathy. Even more concerning is the strong association of gadolinium with nephrogenic systemic fibrosis (NSF), a devastating fibrosing disorder of the skin and other systemic organs. Although cause and effect have not been proven for the NSF-gadolinium link, the impaired renal elimination of gadolinium in patients with kidney disease and the instability of gadolinium-chelate binding may expose tissues to toxic free Gd(3+) and promote this fibrosing disorder. Caution should be exercised when utilizing gadolinium as a contrast agent in patients with advanced chronic kidney disease or end-stage renal disease. /Gadolinium-containing contrast media/
[Perazella MA et al; Semin Dial 20 (3): 179-85 (2007)] **PEER REVIEWED** PubMed Abstract


Interactions:
Macrophages infiltrating injured tissue play an important part in fibrogenesis. To shed light on the functional roles of macrophages, ... the appearance of macrophage populations in thioacetamide (TAA)-induced rat hepatic lesions /was investigated/, with or without pretreatment with GdCl(3), a chemical capable of inhibiting Kupffer cell functions. In the GdCl(3)+TAA group rats received a single ip injection of GdCl(3) (7.5mg/kg body weight) and, after 24 hr, a single intravenous injection of TAA (300 mg/kg body weight). Rats in the TAA group received TAA only. Rats in both groups were examined on post-TAA injection (PTI) days 3, 5, and 7. In the TAA group, on PTI day 3, when TAA-induced hepatocyte injury was particularly prominent, the number of macrophages peaked, subsequently decreasing until PTI day 7. As compared with the TAA group, the GdCl(3)+TAA group showed significantly decreased numbers of ED1-immunolabelled cells (exudate macrophages) and ED2-immunolabelled cells (Kupffer cells) on PTI days 3, 5, and 7, and OX6-immunolabelled cells (antigen-presenting macrophages) on PTI days 3 and 5. Although less strikingly, the numbers of alpha-smooth muscle actin-positive myofibroblasts and fibrotic areas were decreased in the GdCl(3)+TAA group. By RT-PCR, the expression of TGF-beta1 mRNA was suppressed on PTI days 3 and 7 in the GdCl(3)+TAA group, and the suppressed expression was confirmed in vitro by treating rat macrophage-like cells (HS-P) with 1% GdCl(3). The study showed that GdCl(3) treatment decreased the numbers of macrophages appearing in hepatic lesions and inhibited TGF-beta1 mRNA expression in macrophages. Decreased numbers of macrophages may contribute to improvement of hepatic fibrosis. /Gadolinium chloride/
[Ide M et al; J Comp Pathol 133 (2-3): 92-102 (2005)] **PEER REVIEWED** PubMed Abstract

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1 mmol/kg), were intraperitoneally injected with thioacetamide (6.6 mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96 hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNF alpha and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. /It was concluded/ that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. ... /Gadolinium chloride/
[Andres D et al; Biochem Pharmacol 66 (6): 917-26 (2003)] **PEER REVIEWED** PubMed Abstract

Gadolinium chloride (GdCl3) reportedly inhibits Kupffer cell function including TNF-alpha production and thereby improves organ dysfunctions after lipopolysaccharide (LPS) challenge, particularly in partially hepatectomized (PH) mice. In addition, TNF-alpha reportedly promotes the regeneration of hepatocytes after PH. However, /the authors/ have frequently seen GdCl3 treatment increase the mortality of normal mice after LPS injection. ... The mice treated by GdCl3 (10 mg/kg, iv) at 24 hr before LPS challenge showed increased serum TNF-alpha and ALT levels after LPS challenge and a decreased mouse survival rate. The Kupffer cells from GdCl3-treated mice consistently produced a much larger amount of TNF-alpha following in vitro LPS stimulation than those of the control mice despite the fact that the Kupffer cells decreased in number and also demonstrated decreased superoxide production. Anti-TNF-alpha Ab before LPS-injection greatly improved GdCl3-induced mouse mortality and the degree of liver injury. In marked contrast, the increased amount of TNF-alpha induced by GdCl3 improved the survival after LPS challenge in PH mice because TNF-alpha promoted hepatocyte mitosis/regeneration in PH liver as evidenced by the fact that the inhibition of TNF-alpha before PH suppressed hepatocyte regeneration and decreased survival after LPS challenge. In conclusion, GdCl3 depletes the superoxide-producing Kupffer cells but conversely enhances the function of TNF-alpha-producing Kupffer cells, which thereby leads to LPS-induced mortality. Meanwhile, the increased TNF-alpha production induced by GdCl3 supports liver regeneration and increases the survival after LPS challenge in PH mice.
[Kinoshita M et al; Shock 23 (1): 65-72 (2005)] **PEER REVIEWED**