Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging

Eur J Radiol. 1995 Nov;21(1):1-10. doi: 10.1016/0720-048x(95)00679-k.

Abstract

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.

MeSH terms

  • Animals
  • Brain / pathology
  • Brain Neoplasms / diagnosis
  • Cerebral Infarction / diagnosis
  • Contrast Media / pharmacokinetics*
  • Contrast Media / toxicity
  • Dogs
  • Drug Interactions
  • Extracellular Space / metabolism
  • Female
  • Half-Life
  • Injections, Intravenous
  • Lethal Dose 50
  • Magnetic Resonance Imaging*
  • Male
  • Metabolic Clearance Rate / physiology
  • Mice
  • Organometallic Compounds / pharmacokinetics*
  • Organometallic Compounds / toxicity
  • Rats
  • Rats, Wistar
  • Tissue Distribution

Substances

  • Contrast Media
  • Organometallic Compounds
  • gadobutrol