Original contribution The stability of gadolinium-based contrast agents in human serum: A reanalysis of literature data and association with clinical outcomes John P. Prybylski a , Richard C. Semelka b , Michael Jay a, ⁎ a Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 4012 Marsico Hall, Chapel Hill, NC 27599-7362, United States b Department of Radiology, UNC School of Medicine, University of North Carolina at Chapel Hill, 2001 Old Clinic Bldg., Chapel Hill, NC 27599-7510, United States abstract article info Article history: Received 14 December 2016 Received in revised form 6 January 2017 Accepted 7 January 2017 Available online xxxx Purpose: To reanalyze literature data of gadolinium (Gd)-based contrast agents (GBCAs) in plasma with a kinetic model of dissociation to provide a comprehensive assessment of equilibrium conditions for linear GBCAs. Methods: Data for the release of Gd from GBCAs in human serum was extracted from a previous report in the lit- erature and fit to a kinetic dissociation/association model. The conditional stabilities (logK cond ) and percent intact over time were calculated using the model rate constants. The correlations between clinical outcomes and logK cond or other stability indices were determined. Results: The release curves for Omniscan®, gadodiamide, OptiMARK®, gadoversetamide Magnevist® and Multihance® were extracted and all fit well to the kinetic model. The logK cond s calculated from the rate constants were on the order of ~4–6, and were not significantly altered by excess ligand or phosphate. The stability con- stant based on the amount intact by the initial elimination half-life of GBCAs in plasma provided good correlation with outcomes observed in patients. Conclusions: Estimation of the kinetic constants for GBCA dissociation/association revealed that their stability in physiological fluid is much lower than previous approaches would suggest, which correlates well with deposition and pharmacokinetic observations of GBCAs in human patients. © 2017 Published by Elsevier Inc. Keywords: Gadolinium Contrast agents Magnetic resonance imaging Stability Kinetics 1. Introduction Questions about the stability of gadolinium (Gd)-based contrast agents (GBCAs) in vivo have recently received renewed attention fol- lowing reports of Gd deposition in the brains [1,2], skin [3] and bones [4] of patients with normal renal function. While much of the original work in developing these agents for human use was appropriately ded- icated to confirming that the toxic Gd metal was not released [5], the conclusion of acceptable stability was determined to be clearance of not significantly b 100% of injected Gd. The statistics allowed a point av- erage retention of anywhere from 1 to 5% of total dose [6], which we are now finding may have been clinically significant, despite not being sta- tistically significant. At this time, no unconfounded neurological symptoms have been re- ported in patients with autopsy-confirmed Gd deposition in the brain [7], and a recent animal model failed to find any histological evidence of toxicity from deposition [8]. However, in a case with biopsy-con- firmed soft-tissue deposition of Gd, the patient also reported severe joint pain for which the authors did not provide an alternative explana- tion [9]. There is also a growing number of patients with purported Gd toxicity who have experienced elevated urine Gd months after under- going a contrast-enhanced MRI, with a collection of symptoms includ- ing joint pain and an alarming “brain fog,” which can otherwise be described as slowed cognition or perception [10]. There is no strong ev- idence of causality between GBCA exposure, retention and any of the re- ported symptoms, nor is there any evidence of a specific patient population that may be at greater risk of Gd retention or negative out- comes. However, a conservative approach would consider methods to identify and mitigate risks to patients as we attempt to determine cau- sation; rather than attempting to elucidate patient-specific risk factors, it may be more rational to address gaps in the extensive body of evi- dence around GBCAs themselves. Attempts to predict or approximate GBCA stability in vivo have ranged from comparison with Gd salt pharmacokinetics [11], correla- tion with dissociation in acid [5], stability in simulated plasma [12,13] and direct measurement of dissociation in plasma [14]. While each ap- proach has some methodological limitations, direct measurement has the most potential value because it allows adequate control over a phys- iologically relevant system and it will not be confounded by distribution and elimination kinetics (computer simulated plasma would allow complete control over a system without confounding pharmacokinetics, but requires in vitro data to verify the assumptions of the model are valid). A major work assessing the stability of GBCAs in human serum Magnetic Resonance Imaging 38 (2017) 145–151 ⁎ Corresponding author. E-mail address: mjay@unc.edu (M. Jay). http://dx.doi.org/10.1016/j.mri.2017.01.006 0730-725X/© 2017 Published by Elsevier Inc. Contents lists available at ScienceDirect Magnetic Resonance Imaging journal homepage: www.mrijournal.com