Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats

Abstract

Objectives: The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs). Methods: Sixty-five male Sprague-Dawley rats were randomized to four exposure groups (n = 15 per group) and one control group (n = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days’ recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals. Results: Significantly (p ≤ 0.005; all evaluations) lower Gd levels were noted with ProHance® than with Dotarem®, Clariscan™, or Gadovist® in all soft tissue organs: 0.144 ± 0.015 nmol/g vs. 0.342 ± 0.045, 0.377 ± 0.042, and 0.292 ± 0.047 nmol/g, respectively, for cerebrum; 0.151 ± 0.039 nmol/g vs. 0.315 ± 0.04, 0.345 ± 0.053, and 0.316 ± 0.040 nmol/g, respectively, for cerebellum; 0.361 ± 0.106 nmol/g vs. 0.685 ± 0.330, 0.823 ± 0.495, and 1.224 ± 0.664 nmol/g, respectively, for liver; 38.6 ± 25.0 nmol/g vs. 172 ± 134, 212 ± 121, and 294 ± 127 nmol/g, respectively, for kidney; and 0.400 ± 0.112 nmol/g vs. 0.660 ± 0.202, 0.688 ± 0.215, and 0.999 ± 0.442 nmol/g, respectively, for skin. No GBCA-induced macroscopic or microscopic findings were noted in the kidneys. Conclusions: Less Gd is retained in the brain and body tissues of rats 28 days after the last exposure to ProHance® compared to other macrocyclic GBCAs, likely due to unique physico-chemical features that facilitate more rapid and efficient clearance.