Metabolism and pharmacokinetics of MnDPDP in man

Abstract

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 (≤ min). Both groups received 5 and 10 μmol/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.

Dynamic evaluation of the hepatic uptake and clearance of manganese‐based MRI contrast agents: A 31P NMR study on the isolated and perfused rat liver

“…Finally, we did not observe a major transmetallation with zinc during the preincubation of MnDPDP with blood. This difference with the in vivo situation (22), where the fraction of plasma zinc bound to dipyridoxyl ethylenediamine is rapidly restored from tissues, can be attributed to the large excess of complex relative to the minute amount of zinc available in the small volume of blood used in our protocol. plexation of MnDPDP in the perfusion fluid wander Elst et al, unpublished results), which does not contain zinc, another powerful partner for transmetallation.…”

A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism

“…The contrast agent Mn-DPDP has an FDA indication for imaging liver lesions although the product is discontinued (28–31). Mn-DPDP is dissociated upon injection, releasing free Mn into the bloodstream (32), which is then rapidly taken up by liver, pancreas, and myocardium. The DPDP chelator recovered from the urine is near completely stripped of Mn (32).…”

“…Mn-DPDP is dissociated upon injection, releasing free Mn into the bloodstream (32), which is then rapidly taken up by liver, pancreas, and myocardium. The DPDP chelator recovered from the urine is near completely stripped of Mn (32). Despite functioning by releasing free Mn 2+ ion, Mn-DPDP has been used safely in tens of thousands of patients.…”

Tumor models and specific contrast agents for small animal imaging in oncology

“…However, this assumption was later disproved by the observations that after intravenous injection, in the plasma, Mn-DPDP is gradually processed by the following steps: dephosphorylation, transmetallation with endogenous zinc, protein binding to the released Mn 2+ , and eventually hepatocytic uptake of Mn 2+ for rapid blood clearance (Fig. 5) [47]. In addition, little hepatic uptake of the DPDP 2À ligand was observed, which means that the role of DPDP is limited in facilitating intracellular uptake of Mn 2+ [48].…”