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

Abstract

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 degrees C. 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 degrees 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 degrees C [% Gd 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 Gd 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. The release of Gd from all linear Gd3+ 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.