PHARMACOKINETICS AND STABILITY OF CALDIAMIDE SODIUM IN RATS

Gadodiamide (CAS 122795-43-1) injection (Omniscan(R)) is a formulation composed of gadolinium (III) complexed with diethylenetriaminepentaac etic acid bis-methylamide (Gd DTPA-BMA) and the sodium calcium complex of the same ligand, known as caldiamide sodium (GAS 122760-91-2, NaCa DTPA-BMA), in a molar ratio of 20:1. Following intravenous dosing of NaCa DTPA-BMA (0.015 mmol/kg) in a C-14-labeled form, plasma concentra tions of the drug declined rapidly with an elimination half-live of 0. 31 h, a distribution volume of 244 ml/kg and a plasma clearance of 9.2 ml/min/kg. These results demonstrate that NaCa DTPA-BMA distributes i nto the extracellular fluid compartment and is renally excreted via gl omerular filtration. Of the dose of radioactivity given, 86.6% was exc reted in urine by 4 h after injection, and 95.3% in urine and 3.3% in feces by 120 h. In addition, experiments were done to clarify the in v ivo metabolism of NaCa DTPA-BMA. Results show small quantities of tran schelatd forms df NaCa DTPA-BMA in urine. HPLC analysis demonstrated t hese metabolites were the Zn and Cu forms of the drug, resulting from displacement of the Ca ion in the NaCa DTPA-BMA molecule by endogeneou s Zn or Cu. Further analyses by HPLC and ICP-AES demonstrate that the unchanged parent drug, the Zn and the Cu forms occur in relative quant ities of approximately 92%; 7%, and 1%, respectively This demonstrates that the Ca ion in caldiamide sodium can be replaced by Zn or Cu ions in vivo, but only to a small extent.