Preclinical Pharmacokinetics and General Toxicology of Iodixanol

Abstract

To document the safety of iodixanol and to assess its pharmacokinetic properties, extensive tests have been performed. Iodixanol was rapidly excreted, mainly via the kidneys, with a plasma half-life in rats and monkeys of 25 and 76 min, respectively. The pharmacokinetic data were consistent with an extracellular distribution of iodixanol. During the 24 hours post-dosing, the urinary excretion was from 72 to 100% in rats, and 78% in monkeys. Biliary excretion was 1.5% during the first 4 hours in rats. Fecal excretion was about 7% in rats and 0.8% in monkeys over the first 24 hours after injection. Approximately 0.5 and 1% of the dose was found in the kidneys of rats and monkeys, respectively, 24 hours after dosing.

Acute toxicity of iodixanol in rats was low, with an LD₅₀ greater than 21 g I/kg. In mice, the LD₅₀ was 21 g I/kg and the approximated median lethal dose (ALD₅₀) was found to range from 15 to 21 g I/kg. A single dose of 1 and 3 g I/kg was well tolerated in monkeys. As for other roentgen contrast media, a reversible, dose-related, vacuolation of the proximal tubules in the kidneys was seen in the acute and subacute studies in rats and monkeys. No relationship was seen between the vacuolation and kidney function. Local tolerance studies demonstrated a low irritation potential for iodixanol when injected by a variety of intravascular and extravascular routes.

The reproductive capacity of male and female rats was unaffected by iodixanol when administered daily at doses up to 2 g I/kg/day. No teratogenic potential in rats and rabbits of iodixanol was observed. Further, no toxic effects on pups were seen when rats were dosed during the lactation period. Each of 4 standard genotoxicity tests was negative. No antigenic potential of iodixanol was observed when assessed by the passive cutaneous anaphylaxis test and the active systemic anaphylaxis test in guinea pigs.

The intravascular tolerability of iodixanol is high and, therefore, iodixanol should be considered as a safe roentgen contrast medium for intravascular use.