Metabolism of mangafodipir trisodium (MnDPDP), a new contrast medium for magnetic resonance imaging, in beagle dogs.
The metabolism of MnDPDP (manganese(II) N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) was studied in dogs after intravenous infusion for 12.5 min with either 10, 30 or 100 mumol MnDPDP/kg b.w. HPLC analyses of plasma samples obtained 1, 5 and 30 min after the end of infusion revealed that MnDPDP was rapidly dephosphorylated to MnDPMP (manganese(II) N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5-phosphate) and MnPLED (manganese(II) N,N'-dipyridoxylethylenediamine-N,N'-diacetate), with simultaneous transmetallation to the corresponding zinc metabolites ZnDPDP, ZnDPMP and ZnPLED. In the low-dose group, the parent compound MnDPDP was present at the lowest concentration compared to the metabolites at the first sampling time point, 1 min after the end of infusion, whereas MnPLED was the main metabolic. At 30 min post-infusion ZnPLED was the main metabolite. The medium- and high-dose groups showed a similar metabolic pattern. In the high-dose group, MnPLED was the main metabolite at all sampling time points. The estimated plasma half-life of total ligand was 20 min, and it was dose-independent with an apparent volume of distribution of 0.2 l/kg. The rate of dephosphorylation was similar to the rate of transmetallation, and both were dose-independent. However, calculations of the total Mn and Zn ligands indicated that the apparent plasma elimination was dose-dependent. The half-life for total Mn ligands which is a combination of both metabolism and elimination, were 10 and 20 min at 10 and 100 mumol/kg, respectively. The half-life for total Zn ligands which is the half-life for rate of formation of Zn ligands, were 40 and 65 min at 10 and 100 mumol/kg, respectively. No sex differences in metabolic pattern were observed in any of the three dosage groups.
Toft
K G
KG
Research and Development, Nycomed Imaging AS, Oslo, Norway.
Hustvedt
S O
SO
Grant
D
D
Friisk
G A
GA
Skotland
T
T
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000378:metabolism*; D004285:Dogs / Q000378:metabolism*; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D015203:Reproducibility of Results
D003287:Contrast Media; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid