Tissue distribution and general safety of MnDPDP in male beagle dogs, with or without total common bile duct obstruction.
OBJECTIVE
Evaluation of the tissue distribution of manganese (Mn) and general safety in normal and cholestatic male beagle dogs after i.v. administration of mangafodipir trisodium (MnDPDP, Teslascan).


METHODS
Male beagle dogs, with or without surgical obstruction of the common bile duct, received a single i.v. bolus injection of saline (control), or MnDPDP at doses of 10 or 50 mumol/kg b.w. and were sacrificed 1 or 7 days after treatment. Toxicity was assessed and tissue concentrations of Mn were measured.


RESULTS
Increased tissue Mn concentrations were found in all dogs treated with MnDPDP and were greatest in those with biliary obstruction. Although Mn concentrations decreased with time in most tissues in each of the treated groups, this was not the case for the brain and adrenal glands in dogs with total biliary obstruction in which further increases in Mn concentrations were seen at the later time point. This suggested a re-distribution of Mn from the major body depots such as the liver. There were no effects of MnDPDP on clinical signs/behaviour, organ weights, histomorphology or clinical biochemistry.


CONCLUSIONS
These findings indicate that a single clinical dose of 5 mumol/kg MnDPDP is likely to be well tolerated in patients with cholestasis.
Grant
D
D
Nycomed Imaging AS, Oslo, Norway. dgr@nycomed.com
Toft
K G
KG
Martinsen
I
I
Atzpodien
E
E
D000818:Animals; D001651:Cholestasis, Extrahepatic / Q000175:diagnosis / Q000378:metabolism*; D003135:Common Bile Duct / Q000473:pathology; D003287:Contrast Media / Q000009:adverse effects / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004492:Edetic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008026:Ligation; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese / Q000009:adverse effects / Q000493:pharmacokinetics*; D011379:Prognosis; D011732:Pyridoxal Phosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012449:Safety; D014018:Tissue Distribution
D003287:Contrast Media; D008345:Manganese; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid