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.
MnDPDP [manganese(II) N, N'-dipyridoxylethylenediamine- N, N'-diacetate-5,5'-bis(phosphate)] is the active component of Teslascan, a contrast medium for magnetic resonance imaging of the liver. It has previously been shown that MnDPDP is rapidly dephosphorylated to the monophosphate MnDPMP and the non-phosphorylated MnPLED, and that all these substances are rapidly transmetallated to the corresponding Zn complexes. In the present study we used EPR at 9 and 230 GHz to show that no free Mn(2+) ions can be detected in the product or in a mixture of MnDPDP and human serum. Competition experiments between MnDPDP and Zn(2+), Ca(2+), and Mg(2+) ions revealed approximately 15% transmetallation with Zn(2+) in a buffer system containing metal ion concentrations similar to that in serum, whereas approximately 10% transmetallation was obtained with Ca(2+) and only negligible transmetallation was obtained with Mg(2+) under these conditions. Binding experiments with Mn(2+) added to human albumin and human serum indicate that albumin accounts for most of the protein-bound Mn(2+) in serum.
ABSTRACT:The NC100668 consists of a 13-amino acid peptide, N-terminally blocked with an acetyl group containing an iodinated tyrosine and coupled to a Tc-chelator (NC100194) via the C-terminal glycine. Using the common three-letter abbreviations for amino acids, the structure of NC100668 is Acetyl-Asn-Gln-Glu-Gln-Val-Ser-ProTyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194, where NC100194 is represented by the chemical formula -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 . The detailed structure is shown in Fig. 1.99m Tc-NC100668 is being developed as a diagnostic radiopharmaceutical for imaging of venous thromboembolism, which is a major health problem with an estimated average annual incidence in the United States exceeding 1 per 1000 (Silverstein et al., 1998). The peptide moiety of NC100668 is similar to part of the N-terminal sequence in ␣ 2 -antiplasmin (Moroi and Aoki, 1976;Lijnen et al., 1987). The mechanism of action is by covalent linking between a glutamine in ␣ 2 -antiplasmin (corresponding to Gln-2 in NC100668) and a lysine in fibrin mediated by enzymatic action of blood coagulation factor XIIIa (Ichinose et al., 1983;Lee et al., 2001;Jaffer et al., 2004).Diagnostic radiopharmaceuticals are radioactive substances that are administered to patients. Many of these agents are labeled with the ␥-emitter 99m Tc, which has a half-life of 6.02 h (Liu et al., 1997). Due to the short half-life, the 99m Tc-based agents are distributed to hospitals in a Tc-free form as a freeze-dried product ready for labeling with technetium. On the day of the imaging procedure, the 99m Tc is added to the product as the pertechnetate anion TcO 4 Ϫ eluted from a 99 Mo/ 99m Tc generator with saline. The freeze-dried substances are then solubilized in saline in the presence of a reducing agent, which converts the pertechnetate to a lower oxidation state, facilitating coordination to the chelate component of the agent. There is a vast excess of the agent compared with the added Tc as typically less than 1% of the injected agent is in the form of the Tc complex. Hence, the unlabeled agent makes up almost the entire amount of the chemical entity injected, whereas there is only the very small amount of the 99m Tc-labeled agent, which is visualized during the diagnostic imaging procedure. The Tc-free substance is therefore in focus when Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10.1124/dmd.105.006239.ABBREVIATIONS: NC100668, Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194; NC100194, -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 ; Fmoc, 9-fluorenyloxycarbonyl; Boc, butyl oxy carbonyl; PyBOP, benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate; DMF, dimethylformamide; TFA, trifluoroacetic acid; MS, mass spectrometry; HPLC, high-performance liquid chromatography; QWBA, quantitative whole-body autoradiography; SAC, self-absorption coefficient; % ID, percentage of injected dose; LC-MS, liquid chromatography-mass...
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