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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent.

In a wide range of preclinical studies of gadodiamide injection (Omniscan, Sanofi Winthrop, New York, NY, and Nycomed AS, Oslo, Norway), the pharmacokinetics of the compound have been delineated and its safety demonstrated. The pharmacokinetic behavior of gadodiamide was consistent with its extracellular distribution. Its half-life in rats, rabbits, and monkeys was short, 18, 38, and 75 minutes, respectively. Gadodiamide was shown to be excreted rapidly, primarily through the kidneys. In rats, 94% of the administered dose was excreted in the urine within the first 24 hours after administration. Approximately 1% to 4% appeared in the feces during the same period. Gadodiamide injection has been shown to have a remarkably low acute lethal toxicity, superior to that of gadopentetate dimeglumine injection (Magnevist, Berlex Laboratories, Wayne, NJ, and Schering AG, Berlin, Germany) or gadoterate meglumine (Dotarem, Laboratoire Guerbet, Aulnay-Sous-Bois, France). In comparison with gadopentetate dimeglumine injection, gadodiamide injection had fewer effects on cardiovascular and hemodynamic function after rapid intravenous injection in anesthetized dogs and, in vitro at high concentrations, on erythrocyte fragility and arterial wall tension. The lesser effects might be attributable, at least in part, to the lower osmolality of gadodiamide injection, although it remains to be seen whether this will translate into any advantage for gadodiamide injection at the lower doses used for imaging procedures in patients. Similar to all known intravenously administered diagnostic imaging agents, gadodiamide injection produces vacuolization of the proximal tubular cells in the kidney, without any change in renal function. However, the single-dose threshold for this effect is greater than 0.5 mmol/kg in the rat; even after a dose of 10 mmol/kg, the vacuolization was only "moderate" in degree and was shown to have regressed partially during the 7 days after administration. In monkeys, administration of 0.25 mmol/kg daily for 28 days had no effect on the kidney, thus providing reassurance of the wide margin of safety for any effect of this compound on the kidney. Although intended for single administration in patients, gadodiamide injection has been studied extensively in a range of subchronic studies in rats and monkeys. The compound was well tolerated in monkeys even when administered at doses up to 1.25 mmol/kg daily for 28 consecutive days. In rats, significant toxicity occurred only at high doses, particularly in male animals, and the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism. Gadodiamide injection produced no significant irritation when administered by a variety of intravascular and extravascular routes.[1]

References

  1. Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent. Harpur, E.S., Worah, D., Hals, P.A., Holtz, E., Furuhama, K., Nomura, H. Investigative radiology. (1993) [Pubmed]
 
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