Dissociation of gadolinium chelates in mice: Relationship to chemical characteristics

Wedeking, P.; Kumar, Krishan; Tweedle, Michael F.

doi:10.1016/0730-725x(92)90016-s

Cited by 214 publications

(171 citation statements)

References 11 publications

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“…This result is much lower than the error limit in the results of the pharmacokinetic study of [Gd(DTPA)] 2À , in which it was found that within 24 h 91(AE 13) % of the injected dose left the human body. [3] However, our result is comparable with the results of Wedeking et al [5] and Harrison et al, [6] who found the whole body retention of Gd 3 from [Gd(DTPA)] 2À in mice 24 h after the injection was about 1.3 ± 1.4 %. In the equilibrium calculations based on the plasma model, the amount of Gd 3 released was underestimated, because the formation of the dinuclear [Zn 2 (DTPA)] was not taken into account.…”

supporting

confidence: 93%

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

2000

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The kinetic stability of the complex [Gd(DTPA)]2- (H5DTPA = diethylenetriamine-N,N,N',N",N"-pentaacetic acid), used as a contrast-enhancing agent in magnetic resonance imaging (MRI), is characterised by the rates of the exchange reactions that take place with the endogenous ions Cu2+ and Zn2+. The reactions predominantly occur through the direct attack of Cu2+ and Zn2+ on the complex (rate constants are 0.93+/-0.17 M(-1) s(-1) and (5.6+/-0.4) x 10(-2)M(-1) S(-1), respectively). The proton-assisted dissociation of [Gd(DTPA)]2- is relatively slow (k1 = 0.58+/-0.22 M(-1) s(-1)), and under physiological conditions the release of Gd3+ predominantly occurs through the reactions of the complex with the Cu2+ and Zn2+ ions. To interpret the rate data, the rate-controlling role of a dinuclear intermediate was assumed in which a glycinate fragment of DTPA is coordinated to Cu2+ or Zn2+. In the exchange reactions between [Gd-(DTPA)]2- and Eu3+, smaller amounts of Cu2+ and Zn2+ and their complexes with the amino acids glycine and cysteine have a catalytic effect. In a model of the fate of the complex in the body fluids, the excretion and the "dissociation" of [Gd(DTPA)]2- are regarded as parallel first-order processes, and by 10 h after the intravenous administration the ratio of the amounts of "dissociated" and excreted [Gd(DTPA)]2- is constant. From about this time, 1.71% of the injected dose of [Gd(DTPA)]2- is "dissociated". The results of equilibrium calculations indicate that the Gd3+ released from the complex is in the form of Gd3+-citrate.

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supporting

confidence: 93%

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

2000

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“…Various rodent studies have determined the Gd concentrations in several organs after GBCA administration (13,42,(47)(48)(49). In all of these studies the Gd concentrations in the different organs correlated with the complex stability of the administered agent.…”

Section: Role Of Complex Stability: Evaluation Of Marketed Productsmentioning

confidence: 99%

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Sieber

Steger‐Hartmann

Lengsfeld

et al. 2009

Magnetic Resonance Imaging

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Nephrogenic systemic fibrosis (NSF) is a potentially severe systemic disease typically characterized by fibrosis of the skin and connective tissues. The etiology of NSF is still unknown but is likely to be multifactorial. Specific triggers under scientific evaluation have included surgery and/or the occurrence of thrombosis or other vascular injury, proinflammatory state, the administration of high doses of erythropoietin, and more recently the use of gadolinium-based contrast agents (GBCAs). The aim of this review is to summarize knowledge regarding the pathogenesis of NSF and the potential role of GBCAs in its pathology, with a focus on animal experiments. The potential role of complex stability of GCBAs will be highlighted by results from several in vitro and in vivo experiments in rodent models of NSF.

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“…[22][23] It has been previously determined that for hydroxypyridinone-based Gd(III) complexes, maximum stability is obtained with a heteropodal ligand of intermediate basicity comprising one terephthalamide moiety: TRENbisHOPO-TAM. 9 The effect of substituting the terephthalamide podand with solubilizing or targeting group had, however, not yet been determined.…”

Section: Stabilities Of Gd(iii) Complexesmentioning

confidence: 99%

Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules¹

et al. 2006

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Hydroxypyridinone-based Gd(III) complexes have previously been shown to exhibit high relaxivity, especially at the clinically relevant high magnetic fields relevant for present and future clinical use. This is due to more than one coordinated water molecules that exchange rapidly with bulk solvent.. These complexes, however, present poor water-solubility. Heteropodal complexes which include a terephthalamide moiety maintain the high relaxivity characteristics of the HOPO family and have been functionalized with solubilizing substituents of various charges. The charge of the substituent significantly affects the stability of the Gd(III) complex, with the most stable complex presenting a neutral charge. The solubilizing substituent also moderately affects the affinity of the complex for physiological anions, with the highest affinity observed for the positively charged complex. In any case, only two anions, phosphate and oxalate, measureably bind the Gd(III) complex with weak affinities for these two anions that are comparable to other q=1 complexes and much weaker than DO3A, q=2 based complexes. Furthermore, unlike poly(amino-carboxylate) based complexes, HOPO-based Gd(III) complexes do not show any noticeable interaction with carbonates. The nature of the substituent can also favorably stabilize the coordination of a third water molecule on the Gd(III) center and lead to a nine-coordinate ground state. Such complexes that attain q = 3 incorporate a substituent β to the terminal amide of the TAM podand which are hydrogen-bond acceptors, suggesting that the third water molecule is coordinated to the metal center through a hydrogen-bond network. These substituents include alcohols, primary amines, and acids. Moreover, the coordination of a third water molecule has been achieved without destabilizing the complex.

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Dissociation of gadolinium chelates in mice: Relationship to chemical characteristics

Cited by 214 publications

References 11 publications

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules¹

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Dissociation of gadolinium chelates in mice: Relationship to chemical characteristics

Cited by 214 publications

References 11 publications

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

The Rates of the Exchange Reactions between [Gd(DTPA)]2− and the Endogenous Ions Cu2+ and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability of [Gd(DTPA)]2−, Used as a Contrast Agent in Magnetic Resonance Imaging

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules1

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Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules¹