title: Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging.
abstract: OBJECTIVE
  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.
authors.affiliation: Mallinckrodt Imaging, St. Louis, Missouri 63134, USA. jhwible@mkg.com
authors.forename: J H
authors.initials: JH
authors.lastname: Wible
authors.forename: C M
authors.initials: CM
authors.lastname: Troup
authors.forename: M R
authors.initials: MR
authors.lastname: Hynes
authors.forename: K P
authors.initials: KP
authors.lastname: Galen
authors.forename: J R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: S J
authors.initials: SJ
authors.lastname: Barco
authors.forename: J K
authors.initials: JK
authors.lastname: Wojdyla
authors.forename: M P
authors.initials: MP
authors.lastname: Periasamy
authors.forename: M D
authors.initials: MD
authors.lastname: Adams
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D001773:Blood Cells; D002319:Cardiovascular System / Q000187:drug effects; D003287:Contrast Media / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C112666:gadoversetamide