Comparative in vivo dissociation of gadolinium chelates in renally impaired rats: a relaxometry study

Investigation of dissociated versus chelated gadolinium (Gd) in plasma, skin, and bone of rats with impaired renal function after administration of ionic macrocyclic (gadoterate or Dotarem) or nonionic linear (gadodiamide or Omniscan) Gd chelates.

Subtotally nephrectomized Wistar rats were subjected to receive daily injections of 2.5 mmol/kg of Omniscan, gadodiamide without excess ligand caldiamide, Dotarem, or saline (n = 7-10 rats/group) for 5 consecutive days. The Gd concentration was measured by inductively coupled plasma mass spectrometer in skin, femur epiphysis, and plasma on completion of the study (day 11), and dissociated Gd(3+) was measured in the plasma at day 11 (liquid chromatography inductively coupled plasma mass spectrometry). The r(1) relaxivity constant was measured in skin (at day 4 and day 11) and bone (day 11) to investigate the dissociated or chelated form of Gd found in tissue samples. Clinical and skin histopathologic studies were performed.

Subtotal nephrectomy decreased creatinine clearance by 60%. No macroscopic skin lesions were observed in the Dotarem and Omniscan groups in contrast with the gadodiamide group (2 rats survived the study period and 4 of 10 rats showed skin ulcerations and scabs). Skin histopathologic lesions were in the range gadodiamide > Omniscan > Dotarem (similar to control rats). At day 11, the skin Gd concentration was lower in the Dotarem group (161.0 ± 85.5 nmol/g) as compared with the Omniscan (490.5 ± 223.2 nmol/g) and gadodiamide groups (mean value, 776.1 nmol/g; n = 2 survivors). The total Gd concentration in the femur was significantly higher in the Omniscan group than in the Dotarem group. At day 11, the dissociated Gd(3+) concentration in plasma was below the limit of detection in the Dotarem group and was 1.5 ± 0.7 μmol/L in the Omniscan group corresponding to 62% ± 15% of the total Gd concentration. The dissociated Gd(3+) concentration was 1.1 μmol/L in gadodiamide rats (n = 2 survivors). In the skin, the in vivo r1 relaxivity value increased from 4.8 ± 0.7 mM(-1)s(-1) at day 4 to 10.5 ± 3.9 mM(-1)s(-1) at day 11 in the Omniscan group, P < 0.05 (in vitro r(1) in skin, 3.5 mM(-1)s(-1)) and gadodiamide group, whereas no significant change was observed in the Dotarem group (2.8 ± 0.2 and 4.9 ± 2.8 mM(-1)s(-1) at day 4 and 11, respectively, NS) (in vitro value in the skin, 3.2 mM(-1)s(-1)). In the femur, the in vivo r1 relaxivity was higher in the Omniscan group (8.9 ± 2.1 mM(-1)s(-1)) (in vitro relaxivity, 4.5 mM(-1)s(-1)) and gadodiamide group (8.8 mM(-1)s(-1), n = 2 survivors) than in the Dotarem group (3.8 mM(-1)s(-1), n = 1 rat with measurable r(1), since for 7 rats, 1/T(1) - 1/T(1(diamagnetic)) <10% of 1/T(1(diamagnetic)) because of low Gd concentration) (in vitro relaxivity value in the femur matrix, 3.1 mM(-1)s(-1)).

Unlike Dotarem, Omniscan and gadodiamide induced histologic skin lesions. At day 11, a higher Gd concentration was found in both skin and femur of Omniscan- and gadodiamide-treated rats than in Dotarem-treated rats. Relaxometry results indicate gradual in vivo dechelation and release of dissociated Gd(3+) in a soluble form in renally impaired rats receiving Omniscan and gadodiamide, whereas Dotarem remained stable over the study period.