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Metabolism and pharmacokinetics of MnDPDP in man
K G Toft1, S O Hustvedt, D Grant
1Nycomed Imaging AS, Oslo, Norway. ktt@nycomed.com
Purpose:
To study the metabolism and pharmacokinetics of mangafodipir trisodium injection, 0.01 mmol/ml (Teslascan), in healthy male volunteers.
Material And Methods:
Eight volunteers received mangafodipir trisodium as an infusion over 20 min, and 5 received it as an injection (< 1 min). Both groups received 5 and 10 mumol/kg b.w. with a wash-out period of 3 weeks between doses. Metabolites were measured in plasma, total manganese and zinc were measured in plasma and urine and total manganese was measured in faeces.
Results:
The parent compound MnDPDP (manganese dipyridoxyl diphosphate) and 5 metabolites; MnDPMP (manganese dipyridoxyl monophosphate). MnPLED (manganese dipyridoxyl ethylenediamine) and the corresponding zinc compounds ZnDPDP, ZnDPMP and ZnPLED, were detected in plasma. ZnPLED was the only detectable metabolite 8 h after dosing. The apparent volume of distribution of manganese exceeded the interstitial body fluids. The volume of distribution of the ligand indicated distribution to the extracellular fluid only, with the plasma clearance close to the glomerular filtration rate. The manganese was incompletely excreted during the 4 days after treatment with the major part in faeces and less than 20% of the dose in the urine.
Conclusion:
Dephosphorylation and simultaneous transmetallation with zinc are the main metabolic pathways of MnDPDP in man.
Insights
Mangafodipir trisodium (MnDPDP) undergoes dephosphorylation and zinc transmetallation in the body. Manganese is primarily excreted in feces, with limited urinary excretion.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Mangafodipir trisodium (Teslascan) is an MRI contrast agent.
- Understanding its metabolism and pharmacokinetics is crucial for clinical application.
Purpose of the Study:
- To investigate the metabolism and pharmacokinetics of mangafodipir trisodium injection in healthy male volunteers.
- To identify metabolites and determine excretion pathways.
Main Methods:
- Eight volunteers received mangafodipir trisodium via infusion, and five via injection.
- Doses of 5 and 10 mumol/kg were administered with a 3-week washout period.
- Plasma, urine, and fecal samples were analyzed for manganese, zinc, and metabolites.
Main Results:
- The parent compound (manganese dipyridoxyl diphosphate, MnDPDP) and five metabolites, including zinc compounds, were detected in plasma.
- ZnPLED was the sole detectable metabolite 8 hours post-dose.
- Manganese distribution exceeded interstitial fluids, and excretion was incomplete within 4 days, mainly via feces.
Conclusions:
- Dephosphorylation and transmetallation with zinc are the primary metabolic pathways for MnDPDP in humans.
- The pharmacokinetic profile suggests distribution to extracellular fluid and clearance near glomerular filtration rate.