Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37°C


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Abstract

Objectives:Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37°C.Methods and Results:The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37°C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37°C [% Gd3+ release after 15 days and initial rate (%/d) (95% confidence interval) in brackets].Nonionic Linear GBCAs:Optimark [21 (19–22) %, 0.44 (0.40–0.51) %/d) and Omniscan [20 (17–20) %, 0.16 (0.15–0.17) %/d].Ionic Linear GBCAs:Magnevist [1.9 (1.2–2.0) %, 0.16 (0.12–0.36) %/d], Multihance [1.9 (1.3–2.1) %, 0.18 (0.13–0.38) %/d], Vasovist [1.8 (1.4–1.9) %, 0.12 (0.11–0.18) %/d], and Primovist [1.1 (0.76–1.2) %, 0.07 (0.05–0.08) %/d].Macrocyclic GBCAs:Gadovist, Prohance, and Dotarem (all < limit of quantification of 0.1%, <0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd3+ release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs.Conclusions:The release of Gd3+ from all linear Gd complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

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