Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging.

RATIONALE AND OBJECTIVES: A series of preclinical tests were undertaken during the developmental process to determine the safety profile of gadoversetamide injection (OptiMARK). METHODS: Acute intravenous, acute intracisternal, and repeated-dose toxicities; cardiovascular effects; and genetic and reproductive toxicology characteristics were assessed in several animal species. RESULTS: Gadoversetamide injection demonstrated an acute intravenous median lethal dose of 25 to 28 mmol/kg and a maximum nonlethal dose of 14 mmol/kg in mice. In the dog, acute administration of gadoversetamide injection showed a no observable effect level at 3 mmol/kg. Dosed daily for 4 weeks, gadoversetamide injection (0.1 mmol x kg(-1) x d(-1)) caused no serious irreversible changes in any organs in rats and dogs. At a dose of 0.1 mmol/kg, gadoversetamide injection caused no significant (P < 0.05) changes in cardiovascular function in anesthetized dogs. Gadoversetamide injection showed no mutagenic activity. Fertility, reproductive performance, and postnatal fetal development were not affected at doses up to 0.5 mmol x kg(-1) x d(-1) in the rat. No teratogenicity was observed at doses up to 4.2 mmol x kg(-1) x d(-1) in the rat and up to 1.6 mmol x kg(-1) x d(-1) in the rabbit. CONCLUSIONS: Data from our toxicological assessment demonstrate the safety of gadoversetamide injection in a number of animal species at doses exceeding the intended human clinical dose.

Neurotoxicity of non-ionic X-ray contrast media after intracisternal administration in rats.

The neurotoxicity of an X-ray contrast medium appears inversely related to the hydrophilicity of the agent. To further test this hypothesis, four non-ionic X-ray contrast agents, differing in hydrophilicity, (ioversol, iopromide, iohexol and iopamidol) were injected into the cisternal magna of ether-anesthetized rats. Iopromide demonstrated an acute median lethal dose of 122 mg I/kg. Other signs of toxicity included convulsions, apnea, dyspnea and hypoactivity. In contrast, ioversol, iohexol and iopamidol caused no deaths when administered intracisternally, up to a dose of 1000 mg I/kg. Animals treated with these nonionic agents displayed signs of convulsions, apnea, dyspnea, chewing and hypoactivity. Iopromide possesses a hydrophilicity (e.g., water to octanol partition coefficient) approximately 8.5 times smaller than ioversol, 4.6 times smaller than iohexol and 2.3 times smaller than iopamidol. These data support the hypothesis that tri-iodinated X-ray contrast materials with smaller degrees of hydrophilicity produce greater toxicity to the central nervous system.

The effect of sodium on the fibrillatory potential of ioversol.

The spontaneous ventricular fibrillation (VF) potential of the nonionic contrast media, ioversol (IOV), with and without the addition of sodium was examined during right coronary artery (RCA) injections into anesthetized closed-chest dogs. Protocols included fixed volume (6 mL) and fixed rate (0.4 and 0.6 mL/sec) injections to compare two or more of the following: IOV, IOV + (0.075-0.9% wt/vol) NaCl, and sodium/meglumine diatrizoate (DIA). In these studies, the incidence of VF for IOV alone was either greater that with IOV + NaCl formulations or, if equivalent, the incidence of other arrhythmias was greater with IOV alone than with the sodium formulations. When DIA was included in the comparisons, the incidence of VF was always greater than IOV with or without sodium. There was a sodium-related concentration prolongation in QT interval that, at 0.9% NaCl, approximated that with DIA, even though the incidence of VF for the sodium formulation was 0/15 vs. 6/12 for DIA. Thus, the addition of sodium to IOV appears to reduce the propensity for sponteneous VF in the canine model.