Identification

Name
Mangafodipir
Accession Number
DB06796
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Mangafodipir is a contrast agent used as a diagnostic tool administered intravenously to enhance contrast in magnetic resonance imaging (MRI) of the liver and pancreas. It consists of two parts, the paramagnetic manganese (II) ions and the chelating agent fodipir (dipyridoxyl diphosphate, DPDP). Manganese absorption into the tissues that makes the normal tissue appear brighter in MRI is limited in abnormal or cancerous tissue. Enhanced contrast by mangafodipir improves visualization and detection of lesions of the liver formed from metastatic disease or hepatocellular carcinomas. The contrast agent is present as mangafodipir trisodium marketed under the name Teslascan. Teslascan has been removed from the Drug Product List by FDA in 2003, and withdrawn from the European market in 2012.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Mangafodipir trisodium129FW80TG4140678-14-4BENFPBJLMUIGGD-UHFFFAOYSA-I
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TeslascanSolution37.9 mgIntravenousGe Healthcare2000-09-152010-07-26Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
TeslascanMangafodipir trisodium (0.01 mmol/ml)Injection, solutionIntravenousGe Healthcare As1997-05-222012-08-02Eu
TeslascanMangafodipir trisodium (0.01 mmol/ml)Injection, solutionIntravenousGe Healthcare As1997-05-222012-08-02Eu
Categories
UNII
N02W67RKJS
CAS number
155319-91-8
Weight
Average: 691.382
Monoisotopic: 691.06142
Chemical Formula
C22H30MnN4O14P2
InChI Key
CXFKOLCMCRBYPL-UHFFFAOYSA-L
InChI
InChI=1S/C22H32N4O14P2.Mn/c1-13-21(31)15(5-17(23-13)11-39-41(33,34)35)7-25(9-19(27)28)3-4-26(10-20(29)30)8-16-6-18(12-40-42(36,37)38)24-14(2)22(16)32;/h5-6,31-32H,3-4,7-12H2,1-2H3,(H,27,28)(H,29,30)(H2,33,34,35)(H2,36,37,38);/q;+2/p-2
IUPAC Name
manganese(2+) ion 2-({2-[(carboxylatomethyl)({3-hydroxy-2-methyl-6-[(phosphonooxy)methyl]pyridin-4-yl}methyl)amino]ethyl}({3-hydroxy-2-methyl-6-[(phosphonooxy)methyl]pyridin-4-yl}methyl)amino)acetate
SMILES
[Mn++].CC1=C(O)C(CN(CCN(CC([O-])=O)CC2=CC(COP(O)(O)=O)=NC(C)=C2O)CC([O-])=O)=CC(COP(O)(O)=O)=N1

Pharmacology

Indication

Indicated for use as an organ-specific paramagnetic contrast agent developed for imaging of the hepatobiliary system and detecting lesions in liver and pancreas.

Pharmacodynamics

Manganese (II) metals exhibit paramagnetic properties that increases contrast between normal liver parenchyma and metastatic liver lesions after uptake into the hepatic or pancreatic parencyma. They serve to increase the signal intensity of liver or pancreas tissue. Enhancement in both organs is near maximal for up to approximately 4 hours after the end of administration. Lesion-related enhancement of certain types of lesions, such as liver metastases and hepatocellular carcinomas, may be detectable for up to 24 hours [8].

Mechanism of action

After intravenous administration, the chelate dissociates slowly to manganese and organic ligand fodipir (dipyridoxyl diphosphate), and manganese is taken up by the hepatocytes with high affinity and selectivity. The ligand fodipir is distributed to the extracellular fluid and later eliminated via urine [3]. Mangafodipir shortens the longitudinal relaxation time (T1) of targeted tissues during MRI, where signal intensity or brightness is increased in normal liver parenchyma. Overall, there is increased contrast between normal tissue and abnormal tissue with lesions because there is a difference between cellular compositions [6], and manganese uptake in metastatic tissue or focal lesions is minimal or nearly absent [1].

Absorption

Mangafodipir is taken up by the liver and pancreas where the contrast enhancement effect is mediated.

Volume of distribution

The volume of distribution for manganese is between 0.5 and 1.5 l/kg, and 0.17 to 0.45 l/kg for fodipir (dipyridoxyl diphosphate) [8]. Fodipir is distributed rapidly throughout the body with the highest concentrations in the kidneys, lung, blood and liver with a low affinity in the myocardium and brain. Manganese is initially distributed to the kindeys and sequentially to liver, spleen and pancreas [9].

Protein binding

The protein binding of manganese is approximately 27% but negligible for fodipir [8]. Manganese is transported to the liver via α2-macroglobulin and to a lesser extent, albumin [3].

Metabolism

Mangafodipir (MnDPDP) is dephosphorylated to form Mn dipyridoxyl monophosphate (MnDPMP) and fully dephosphorylated Mn dipyridoxyl ethylenediamine diacetate (MnPLED) in a sequential manner, followed by simultaneous transmetallation where maganese is exchanged for plasma zinc [8]. Corresponsing zinc compounds are ZnDPDP, ZnDPMP and ZnPLED [3]. Manganese is released from the complex to be transported to target organs.

Route of elimination

Fodipir is predominantly eliminated via urine within 24 hours where up to 25% of administered fodipir is excreted into feces. Manganese is mainly excreted into feces where renal elimination is about 15-20% of the dose [9].

Half life

The mean initial plasma half-life of manganese metals is approximately 20 minutes and 50 minutes for fodipir (dipyridoxyl diphosphate, DPDP) [8].

Clearance

The approximate total clearance of radiolabeled mangafodipir is 3.1 mL/min kg in dogs [4].

Toxicity

Common adverse effects include headache, nausea and feeling of warmth or flushing. Other uncommon side effects include hypersensitivity reactions, fever, diarrhea, vomiting, dizziness, palpitations, paraesthesia, abdominal pain, and taste sensations. There is no identified antidote in case of overdose. Mangafodipir displays embryotoxic and fetotoxic potential thus is contradindicated in pregnant patients. It is not reported to be genotoxic [9]. LD50 in the mouse is 5 mmol/kg [7].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AclidiniumMangafodipir may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineMangafodipir may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Mangafodipir which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Wang C: Mangafodipir trisodium (MnDPDP)-enhanced magnetic resonance imaging of the liver and pancreas. Acta Radiol Suppl. 1998;415:1-31. [PubMed:9571956]
  2. Hirt D, Richardet JP, Urien S, Poupon J, Sogni P, Batteux F, Laurent A, Pavlovic S, Debray M, Treluyer JM, Weill B: Pharmacokinetic-pharmacodynamic modeling of manganese after a single intravenous infusion of mangafodipir in patients with acute alcoholic hepatitis. Ther Drug Monit. 2009 Oct;31(5):557-65. doi: 10.1097/FTD.0b013e3181affd6d. [PubMed:19834427]
  3. Toft KG, Hustvedt SO, Grant D, Martinsen I, Gordon PB, Friisk GA, Korsmo AJ, Skotland T: Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol. 1997 Jul;38(4 Pt 2):677-89. [PubMed:9245963]
  4. Hustvedt SO, Grant D, Southon TE, Zech K: Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration. Acta Radiol. 1997 Jul;38(4 Pt 2):690-9. [PubMed:9245964]
  5. Eser G, Karabacakoglu A, Karakose S, Eser C, Kayacetin E: Mangafodipir trisodium-enhanced magnetic resonance imaging for evaluation of pancreatic mass and mass-like lesions. World J Gastroenterol. 2006 Mar 14;12(10):1603-6. [PubMed:16570354]
  6. Karabacakoglu A, Adiguzel Y, Karakose S, Kayacetin E, Haykir R: Characterization of focal liver lesions: use of mangafodipir trisodium (MnDPDP)-enhanced MR images. Turk J Gastroenterol. 2006 Sep;17(3):164-71. [PubMed:16941248]
  7. Colet JM, Vander Elst L, Muller RN: 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. J Magn Reson Imaging. 1998 May-Jun;8(3):663-9. [PubMed:9626883]
  8. European Medicines Agency (EMA): TESLASCAN Summary of Product Characteristics [Link]
  9. European Medicines Agency (EMA): TESLASCAN Scientific Discussion [Link]
External Links
PubChem Compound
131704299
PubChem Substance
310264892
ChemSpider
32700460
Wikipedia
Mangafodipir
ATC Codes
V08CA05 — Mangafodipir

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingDiagnosticDisseminated Sclerosis / Optic Neuritis1
1SuspendedDiagnosticEpilepsies1
2CompletedTreatmentMalignancies / Neurotoxic Disorders1
2CompletedTreatmentCancer treatment / Malignant Neoplasm of Colon1
2CompletedTreatmentMyocardial Infarction1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous0.01 mmol/ml
SolutionIntravenous37.9 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.06 mg/mLALOGPS
logP0.79ALOGPS
logP-1.8ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)1.38ChemAxon
pKa (Strongest Basic)-6.4ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count16ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area286.5 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity164.24 m3·mol-1ChemAxon
Polarizability56.97 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Activator
General Function
Superoxide dismutase activity
Specific Function
Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name
SOD2
Uniprot ID
P04179
Uniprot Name
Superoxide dismutase [Mn], mitochondrial
Molecular Weight
24721.955 Da
References
  1. Hirt D, Richardet JP, Urien S, Poupon J, Sogni P, Batteux F, Laurent A, Pavlovic S, Debray M, Treluyer JM, Weill B: Pharmacokinetic-pharmacodynamic modeling of manganese after a single intravenous infusion of mangafodipir in patients with acute alcoholic hepatitis. Ther Drug Monit. 2009 Oct;31(5):557-65. doi: 10.1097/FTD.0b013e3181affd6d. [PubMed:19834427]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Tumor necrosis factor binding
Specific Function
Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for differen...
Gene Name
A2M
Uniprot ID
P01023
Uniprot Name
Alpha-2-macroglobulin
Molecular Weight
163289.945 Da
References
  1. Toft KG, Hustvedt SO, Grant D, Martinsen I, Gordon PB, Friisk GA, Korsmo AJ, Skotland T: Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol. 1997 Jul;38(4 Pt 2):677-89. [PubMed:9245963]
  2. Hustvedt SO, Grant D, Southon TE, Zech K: Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration. Acta Radiol. 1997 Jul;38(4 Pt 2):690-9. [PubMed:9245964]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Toft KG, Hustvedt SO, Grant D, Martinsen I, Gordon PB, Friisk GA, Korsmo AJ, Skotland T: Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol. 1997 Jul;38(4 Pt 2):677-89. [PubMed:9245963]
  2. Hustvedt SO, Grant D, Southon TE, Zech K: Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration. Acta Radiol. 1997 Jul;38(4 Pt 2):690-9. [PubMed:9245964]

Transporters

Kind
Protein
Organism
Homo sapiens
Pharmacological action
Unknown
Actions
Substrate
General Function
Zinc ion transmembrane transporter activity
Specific Function
Important in metal transport, in particular iron. Can also transport manganese, cobalt, cadmium, nickel, vanadium and lead. Involved in apical iron uptake into duodenal enterocytes. Involved in iro...
Gene Name
SLC11A2
Uniprot ID
P49281
Uniprot Name
Natural resistance-associated macrophage protein 2
Molecular Weight
62265.195 Da
References
  1. Madejczyk MS, Boyer JL, Ballatori N: Hepatic uptake and biliary excretion of manganese in the little skate, Leucoraja erinacea. Comp Biochem Physiol C Toxicol Pharmacol. 2009 May;149(4):566-71. doi: 10.1016/j.cbpc.2008.12.009. Epub 2008 Dec 24. [PubMed:19141331]

Drug created on September 14, 2010 10:21 / Updated on November 02, 2018 08:50