Rationale and objectives: The authors studied the long-term distribution of gadolinium (Gd) in mice and rats after the administration of four commercially available magnetic resonance imaging contrast media. The goals were to determine any possible product dissociation in vivo and to evaluate the effects that product excipients had on the tissue distributions.
Methods: Gadolinium-153 (153Gd)-labeled gadopentetate (Magnevist), gadoteridol (ProHance), gadoterate (Dotarem), and gadodiamide (Omniscan) were administered intravenously to mice (0.48 mmol/kg) and rats (0.1 mmol/kg). At various times up to 14 days posttreatment, the residual 153Gd was measured in selected tissues. The tissue distributions obtained were used to make intra- and interchelate distribution evaluations and comparisons regarding tissue clearance and any possible in vivo dissociation of the Gd chelates.
Results: Differences were found among the chelates studied relative to the amounts of residual 153Gd present in tissues known to sequester free Gd, particularly in liver and femur at 7 and 14 days after administration, in both mice and rats. The pattern of the 153Gd distribution suggested that the linear chelates, gadopentetate and gadodiamide, dissociated in vivo resulting in more 153Gd present in bone and liver at the longer residence times than in the subjects injected with the macrocyclic chelates, gadoteridol and gadoterate. The only excipient found to affect the distribution profile was calcium(DTPA-BMA); this excipient in formulated gadodiamide decreased the amounts of residual Gd measured in whole body, bone, and liver in mice compared with levels obtained when gadodiamide was injected alone.
Conclusions: The molecular feature found to be most important in differentiating the four chelates evaluated is the presence or absence of a macrocyclic structure. The Gd chelates containing this structure, gadoteridol and gadoterate, have the lowest residual Gd at long residence times in both mice and rats. The order of residual whole body Gd at 14 days (lowest to highest) was: gadoteridol integral of gadoterate < or = gadopentetate << gadodiamide. The only excipient that affected the biodistribution was found in the gadodiamide formulation where the addition of 5% calcium (DTPA-BMA) reduced residual Gd to just less than 10 times greater than that found for the macrocyclic chelates with the lowest residual Gd, gadoteridol and gadoterate.