Evidence for weak protein binding of commercial extracellular gadolinium contrast agents

It is widely assumed that commercial extracellular gadolinium-based contrast agents do not bind to proteins. Here, nuclear magnetic relaxation dispersion was used to characterize the interaction between the contrast agents gadodiamide and gadopentetate dimeglumine and the proteins human serum albumin, chicken egg white lysozyme, egg white proteins, or milk proteins. In all cases, contrast agent relaxivity was increased at all field strengths measured (0.0002 to 1.4 T) when protein was added. A distinct peak in relaxivity was observed between 0.5 and 0.7 T that is consistent with fractional protein binding and that could not be attributed to changes in solution viscosity. This peak was observed for gadodiamide with all four protein solutions and for gadopentetate dimeglumine with lysozyme, human serum albumin, and milk proteins. Protein binding was both contrast agent and protein dependent. For gadodiamide, the highest affinity was to egg white and milk proteins, while gadopentetate dimeglumine interacted most strongly with lysozyme. Protein binding was estimated at 30-40% for a 0.7 mmol/kg solution of gadodiamide in egg white or milk proteins. These results have implications for the accurate determination of contrast agent concentration in vivo. Weak protein binding may be an additional discriminating factor in understanding differences in the toxicokinetics of contrast agents.