Role of thermodynamic and kinetic parameters in gadolinium chelate stability

Abstract

In recent years there has been a renewed interest in the physicochemical properties of gadolinium chelates (GC). The aim of this review is to discuss the physicochemical properties of marketed GC with regard to possible biological consequences. GC can be classified according to three key molecular features: 1) the nature of the chelating moiety: either macrocyclic molecules in which Gd 3þ is caged in the preorganized cavity of the ligand, or linear, openchain molecules; 2) ionicity: the ionicity of the molecule varies from neutral to tri-anionic agents; and 3) the presence or absence of an aromatic lipophilic moiety, which has a profound impact on the biodistribution of the GC. These parameters can also explain why GC differ considerably with regard to their thermodynamic stability constants and kinetic stability, as demonstrated by numerous studies. The concept of thermodynamic and kinetic stability is critically discussed, as it remains somewhat controversial, especially in predicting the amount of free gadolinium that may result from decomplexation of chelates in physiologic or pathologic situations. This review examines the possibility that the high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) can minimize the amount of free Gd 3þ released in the body.

Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

“…the fact that all GBCAs independently of their chemical structure initially reach the cerebellum and pons, leads to the hypothesis that the GBCA complex stability plays a role during further elimination from this brain structures. The different chemical structures exhibit different thermodynamic and kinetic complex stabilities [38, 39], apparently allowing for greater release of Gd 3+ at physiological conditions with linear than with macrocyclic GBCAs [40]. However, to assess the role of complex stability, the chemical species of gadolinium in the brain has to be evaluated.…”

Trace element analysis of human urine collected after administration of Gd-based MRI contrast agents: characterizing spectral interferences using inorganic mass spectrometry

“…25 For this reason it is desirable that the specific ligand used to chelate the Gd 3+ results in a complex with a high thermodynamic stability constant that is therefore kinetically inert. 25 Adding to the complexity of MRI contrast agent behavior after administration, the chelate may undergo a competitive ligand reaction resulting in Gd metal ion exchange 26, 27 with endogenous metals such as Zn. The process by which a Gd ion is exchanged by a chelate for an in vivo metal ion is referred to as transmetallation.…”

Analytical Interference in Serum Iron Determination Reveals Iron Versus Gadolinium Transmetallation With Linear Gadolinium-Based Contrast Agents

“…The serum Gd concentration range tested was selected on the basis of human pharmacokinetic data. The pharmacokinetics of GBCAs is classically described by a 2-compartment model 18. A maximum concentration of 2.5 mM could be expected in the intravascular compartment (for a circulating serum volume of 40 mL/kg) immediately after bolus intravenous administration of a GBCA clinical dose of 0.1 mmol/kg (for a body weight of 70 kg), assuming a strictly intravascular distribution 3.…”