**Table 3.**

*Physiochemical properties of formulations of gadolinium complexes.*


### **Table 4.**

*Thermodynamic stability constants and relaxivities.*

### **Figure 1.**

*Gadopentetate dimeglumine, Gd-DTPA (Magnevist).*

**Gadolinium-DTPA-diamides**: Two extracellular contrast agents that contain neutral gadolinium chelates have entered the market: gadodiamide, Gd-DTPA-BMA (Omniscan) (**Figure 2**), and gadoversetamide (Optimark) (**Figure 3**). Both ligands are amides of DTPA and are obtained by treating the dianhydride of DTPA, corresponding to amine. These gadolinium complexes are freely soluble in water. As expected, the osmolality of the 0.5 molar solution of gadodiamide is lower (0.79 osmol/kg water) than that of the 0.5 molar solution of Gd-DTPA.

**53**

**Figure 4.**

*Gadoterate, Gd-DOTA (Dotarem).*

*Current Clinical Issues: Deposition of Gadolinium Chelates*

*DOI: http://dx.doi.org/10.5772/intechopen.91260*

*Gadodiamide, Gd-DTPA-BMA (Omniscan).*

**2.2 Macrocyclic chelates**

*Gadoversetamide (Optimark).*

**Figure 2.**

**Figure 3.**

a higher kinetic stability [10].

**Gadolinium-DOTA**: The second generation of GBCAs contains the derivatives of the macrocyclic tetramine, 1.4.7.10-tetraazacyclododecane (cyclen). Gadoterate, Gd-DOTA (Dotarem, **Figure 4**), was the first macrocyclic gadolinium complex that was released in the market. In the macrocyclic structure, the metal-binding site within the ligand is more encapsulated, and the entropy is decreased upon metal incorporation. According to previous results, the stability of macrocyclic metal chelates is higher than that of linear complexes. The macrocyclic complexes exhibit

*Current Clinical Issues: Deposition of Gadolinium Chelates DOI: http://dx.doi.org/10.5772/intechopen.91260*

**Figure 2.** *Gadodiamide, Gd-DTPA-BMA (Omniscan).*

*Rare Earth Elements and Their Minerals*

*GBCA: Gadolinium-based contrast agent.*

*Thermodynamic stability constants and relaxivities.*

*Gadopentetate dimeglumine, Gd-DTPA (Magnevist).*

*Physiochemical properties of formulations of gadolinium complexes.*

**GBCAS log K (therm) 1/T1 relaxivity (1/mmol<sup>−</sup><sup>1</sup>**

**Table 3.**

**Table 4.**

**GBCAs Concentration** 

**(mmol/l)**

**Osmolality (osmol/kgH2O)**

1.0 1.90 3.9 [19]

1.0 4.02 11.3 [19]

1.0 1.91 3.9 [19]

1.0 1.39 3.7 [20]

Gd-DTPA 0.5 1.96 2.9 [20] Gd-DTPA-BMA 0.5 0.79 1.4 [18, 20]

Gd-DOTA 0.5 1.35 2.0 [19]

Gd-HP-DO3A 0.5 0.63 1.3 [19]

Gd-DO3A-butrol 0.5 0.57 1.4 [18]

Gd-DTPA 22.2 3.8 [18] Gd-DTPA-BMA 16.9 3.9 [21] Gd-DOTA 24.7 3.5 [21] Gd-HP-DO3A 23.8 3.7 [21] Gd-DO3A-butrol 21.8 3.6 [18]

**Viscosity References**

**)s<sup>−</sup><sup>1</sup> References**

**52**

Gd-DTPA.

**Figure 1.**

**Gadolinium-DTPA-diamides**: Two extracellular contrast agents that contain neutral gadolinium chelates have entered the market: gadodiamide, Gd-DTPA-BMA (Omniscan) (**Figure 2**), and gadoversetamide (Optimark) (**Figure 3**). Both ligands are amides of DTPA and are obtained by treating the dianhydride of DTPA, corresponding to amine. These gadolinium complexes are freely soluble in water. As expected, the osmolality of the 0.5 molar solution of gadodiamide is lower (0.79 osmol/kg water) than that of the 0.5 molar solution of

**Figure 3.** *Gadoversetamide (Optimark).*

### **2.2 Macrocyclic chelates**

**Gadolinium-DOTA**: The second generation of GBCAs contains the derivatives of the macrocyclic tetramine, 1.4.7.10-tetraazacyclododecane (cyclen). Gadoterate, Gd-DOTA (Dotarem, **Figure 4**), was the first macrocyclic gadolinium complex that was released in the market. In the macrocyclic structure, the metal-binding site within the ligand is more encapsulated, and the entropy is decreased upon metal incorporation. According to previous results, the stability of macrocyclic metal chelates is higher than that of linear complexes. The macrocyclic complexes exhibit a higher kinetic stability [10].

**Figure 4.** *Gadoterate, Gd-DOTA (Dotarem).*

**Figure 5.** *Gadobutrol (Gadovist).*

**Gadolinium-DO3A**: The nonionic open-chain metal chelates and neutral macrocyclic gadolinium chelates have been synthesized. Two of them such as gadobutrol (Gadovist) (**Figure 5**) and gadoteridol (ProHance) (**Figure 6**) have been launched as extracellular MRI contrast agents. Both agents are derivatives of 1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A).

Thermodynamic stability constants and relaxivities in water at 20 MHZ and 40°C of commercially available gadolinium chelates.

## **3. Nephrogenic systemic fibrosis (NSF)**

Nephrogenic systemic fibrosis (NSF) is a multi-systemic fibrosing disease that has been characterized by thickening and tightening of the skin and subcutaneous tissues. NSF also includes fibrosis of the skeletal muscle, lung, liver, testis, or myocardium with possible fatal outcomes.

First described in 1997, NSF was initially known as nephrogenic fibrosing dermopathy because of its classic presentation of symmetric, brawny, or erythematous indurated cutaneous plaques that develop in the setting of renal insufficiency [13, 22, 23]. Grobner's published case reports have found an association of NSF with GBCAs exposure when a meticulous chart review was performed. Currently, over 250 documents reporting NSF cases have been registered by Shawn Cowper of Yale University, which have linked 85% of its cases to gadodiamide (Omniscan) [23–25].

**55**

*Current Clinical Issues: Deposition of Gadolinium Chelates*

The exact pathogenesis of NSF is still unclear. However, there are some evidences suggesting that it likely involves the migration of CD34 and procollagen-1 positive, circulating fibrocytes from the blood to the engaged tissue as proposed by Cowper. These fibrocytes likely activate a fibrotic response through cytokine production and T-cell activation. Several reports have shown increased expression of transforming growth factor β1 and CD68-factor XIIIa within the affected skin and skeletal muscle which are also essential markers associated with wound healing

In addition, evidence of in vivo transmetallation has been provided by a preclinical trial in which rats exposed to repeated high-dose GBCAs injection developed an NSF-like skin lesion consisting of epidermal ulceration, acanthosis, dermal fibrosis, and CD34 fibrocytic infiltration with high concentrations of gadolinium in the skin. These findings were more severe with gadodiamide (Omniscan) than gadopentetate (Magnevist) [28]. The differences in conditional thermodynamic stability constants and stimulatory response of gadodiamide on fibroblasts may explain the higher incidence of NSF with gadodiamide (Omniscan). The medical literature report of NSF and this additional evidence seem to indicate a stratified risk within the class of GBCAs. The transmetallation of the gadolinium chelate would occur because of exchange of Gd3+ ions for endogenous metals (such as Zn, Cu, and Ca), and then free Gd3+ ions are released from the chelate. Patients with severe or end-stage renal disease are more likely to undergo in vivo transmetallation because of markedly prolonged clearance of GBCA. This theory has been substantiated by detection of gadolinium within tissue months after GBCA exposure. And transmetallation of Gd-DTPA with endogenous Fe(II)/Fe(III) is possible in human blood plasma. Telgmann concluded that transmetallation may be a trigger of NSF if free Fe(III) ions were accessible during a prolonged pathway of Gd complexes with linear

1.Onset: A few days to 20 years later. The early clinical symptoms of NSF include pain, pruritus, swelling, erythema (usually starts in the legs), transient alopecia, as well as gastrointestinal symptoms of nausea, vomiting, diarrhea, and

2.Lately, main symptoms emerge such as nodules developing on the skin; thickened skin and subcutaneous tissues, "woody" texture and brawny plaques; joint regulation; and severe pain. Additionally, the fibrosis process involves the internal organs, e.g., muscle, diaphragm, heart, liver, and lungs. All these processes could lead to joint contractures, cachexia, and death, in a proportion

High-risk patients have a history of CKD 4 and 5 (glomerular filtration rate (GFR) < 30 ml/min), dialysis, and with reduced renal function who have had or are awaiting liver transplantation. The lower risk includes patients with CKD 3 (GFR 30–59 ml/min) and children under 1 year, because of their immature renal function [22]. Younger children and elderly persons are not affected by NSF because their immune system is immature [23]. Although the pathogenesis is not revealed, the

immune system might have a key role in inducing NSF.

*DOI: http://dx.doi.org/10.5772/intechopen.91260*

ligands through the patient's body [29].

*3.1.1 Clinical features of NSF*

abdominal pain.

of patients [12, 24].

**3.2 Risk patients**

**3.1 Pathogenesis of NSF**

and fibrosis [26, 27].
