Metabolism and pharmacokinetics of MnDPDP in man.

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.

Mangafodipir trisodium injection, a new contrast medium for magnetic resonance imaging: detection and quantitation of the parent compound MnDPDP and metabolites in human plasma by high performance liquid chromatography.

Manganese(II) dipyridoxyl diphosphate (MnDPDP) is the active component of mangafodipir trisodium injection (Teslascan), a new contrast medium for magnetic resonance imaging. A high performance liquid chromatography (HPLC) method was developed for the simultaneous determination of MnDPDP and its five major metabolites in human plasma, i.e. the dephosphorylation products MnDPMP (manganese(II) dipyridoxyl monophosphate) and MnPLED (manganese(II) dipyridoxyl ethylenediamine diacetate) and the corresponding substances obtained after transmetallation with zinc (ZnDPDP, ZnDPMP and ZnPLED). Heparinized blood samples from patients receiving mangafodipir trisodium injection were immediately mixed with solid trisodium phosphate dodecahydrate to obtain pH 10.0 +/- 0.2 in order to inhibit further in vitro dephosphorylation and transmetallation. The plasma thus obtained was ultrafiltrated prior to HPLC analysis. The chromatographic separation was obtained using a mixed-bed resin with both anion exchange and reversed-phase functions (OmniPac PAX-500) using isocratic elution and UV detection at 310 nm. With an injection volume of 50 microliters, the limit of quantitation (LOQ) values were 0.8-2.3 microM for the Mn compounds and 0.1-0.8 microM for the Zn compounds. The between-run accuracy of spiked plasma samples was in the range 97.5-106.7% with a precision in the range 3.1-9.0%. The best fit calibration curves were obtained using non-linear regression according to the equation Y = A + BXM in the concentration range from LOQ to 100 microM. Long-term storage of spiked plasma samples for three months at -20 degrees C demonstrated the required stability with recovery values within 85-115% of MnDPDP and its five metabolites.

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.