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Kappadione

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Identification

Generic Name
Kappadione
DrugBank Accession Number
DB09332
Background

Kappadione is a Vitamin K derivative (chemically, it is menadiol sodium diphosphate), previously approved by FDA prior to 1982 and marketed by Lilly Marketing for this drug has been discontinued and is not available in North America 3. It has been found to have carcinogenic potential in mammalian cells as well as cytotoxic properties 4. Studies involving the active metabolite of this formulation, menadione, showed oocyte toxicity in a study of mice 4.

Type
Small Molecule
Groups
Approved
Structure
Similar Structures
Weight
Average: 422.084
Monoisotopic: 421.92851833
Chemical Formula
C11H8Na4O8P2
Synonyms
  • Menadiol sodium diphosphate
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Pharmacology

Indication

Anticoagulant-induced prothrombin deficiency caused by coumadin or indanedione derivatives, prophylaxis and therapy of hemorrhagic disease of the newborn, hypoprothrombinemia due to antibacterial therapy, hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K (for example, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, and regional enteritis, other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism) 5,6.

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Pharmacodynamics

Menadiol sodium diphosphate is a highly water-soluble vitamin K analog. The presence of vitamin K is necessary for the formation of prothrombin, factor VII, factor IX and factor X. Lack of vitamin K results in an increased risk of hemorrhage, which can be minor or life-threatening 10.

Mechanism of action

Menadiol sodium phosphate (vitamin K3) is involved as a cofactor in the posttranslational gamma-carboxylation of glutamic acid residues of various proteins in the body, allowing for propagation of the clotting cascade that results in coagulation. These proteins are comprised of the vitamin K-dependent coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor), X (Stuart factor), protein C, protein S, protein Zv and a growth-arrest-specific factor (Gas6). The two vitamin K-dependent proteins found in bone are osteocalcin, also known as bone G1a (gamma-carboxyglutamate) protein or BGP, and the matrix G1a protein or MGP. Gamma-carboxylation is catalyzed by the vitamin K-dependent gamma-carboxylases. The reduced form of vitamin K, vitamin K hydroquinone, is the actual cofactor for the gamma-carboxylases. Proteins containing gamma-carboxyglutamate are called G1a proteins 12.

TargetActionsOrganism
UProthrombin
agonist
Humans
UCoagulation factor VII
agonist
Humans
UCoagulation factor IX
agonist
Humans
UCoagulation factor X
agonist
Humans
UVitamin K-dependent protein C
agonist
Humans
UVitamin K-dependent gamma-carboxylase
agonist
Humans
UVitamin K-dependent protein S
agonist
Humans
Absorption

Menadiol sodium phosphate (vitamin K3), the synthetic analog of vitamin K, being water soluble, is advised in intestinal malabsorption or in states in which bile flow is deficient. The primary disadvantage is that it takes 24 h to initiate therapeutic effects, however, this effect lasts for several days. The dose is 5–40 mg orally, daily. Menadiol sodium phosphate, even in moderate doses, may lead to hemolytic anemia and, for this reason, neonates should not receive this medication. This precautionary measure is valid especially those that are deficient in glucose 6-phosphate dehydrogenase (G6PD); their immature livers are unable to compensate for the heavy bilirubin load and there is an increased risk of kernicterus 9.

Volume of distribution

In a study of rabbits, the apparent volume of distribution (V(d)/F) in plasma was 30.833 ± 12.835 L 13.

Protein binding

Not Available

Metabolism

Menadione or 2-methyl-1,4-naphthoquinone is a synthetic vitamin K analog, undergoes 1-electron reduction by enzymes such as microsomal NADPH–cytochrome P450 reductase and mitochondrial NADH–ubiquinone oxidoreductase (complex I), resulting in redox cycling, or it detoxification via two-electron reduction by NAD(P)H–quinone oxidoreductase 1.

Vitamin K is a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and in 3 synthetic forms): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofactor in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NADPH dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To end the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include various important coagulation factors, such as prothrombin. Warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase 12.

Route of elimination

Vitamin K is heavily metabolized in the liver and excreted in the urine and bile. In tracer studies, it was found that approximately 20% of an injected dose of phylloquinone (Vitamin K metabolite) was found in the urine whereas about 40-50 % was excreted in the feces via the biliary system. The proportion of drug excreted was the same regardless of whether the injected dose was 1 mg or 45 µg. It can, therefore, be inferred that about 60-70% percent of the amounts of phylloquinone absorbed from each vitamin-K containing meal will be lost to the body by excretion 14.

Two major human excretion products have been identified: carboxylic acids with 5 and 7-carbon sidechains that are excreted in the urine as glucuronide conjugates. The biliary metabolites have not been clearly identified but are initially excreted as water-soluble conjugates and become lipid soluble during their passage through the gut, probably through deconjugation by the gut flora. There is no evidence for body stores of vitamin K being conserved by an enterohepatic circulation. Vitamin K itself is too lipophilic to be excreted in the bile and the sidechain-shortened carboxylic acid metabolites are not biologically active 14.

Half-life

Mean elimination half-life of menadione was 27.17 min in the plasma of rabbits, in one study 15.

Clearance

The plasma clearance (CL/F) of VK3 was 0.822 ± 0.254 L min-1. 13

Adverse Effects
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Toxicity

This medication has been associated with increased risk of kernicterus and hemolytic anemia in premature infants 8. It is not advisable to administer this medication in newborns and those with G6PD, due to free radical cycling by this medication. This increases risk of free radical damage to the liver and hemolytic anemia 14.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Products

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International/Other Brands
AQUA Mephyton / Mephyton / Synkavite

Categories

Drug Categories
Not Available
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Naphthalenes
Sub Class
Not Available
Direct Parent
Naphthalenes
Alternative Parents
Aryl phosphomonoesters / Organooxygen compounds / Organic sodium salts / Organic oxides / Hydrocarbon derivatives
Substituents
Aromatic homopolycyclic compound / Aryl phosphate / Aryl phosphomonoester / Hydrocarbon derivative / Naphthalene / Organic alkali metal salt / Organic oxide / Organic oxygen compound / Organic phosphoric acid derivative / Organic salt
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
R2L46WE615
CAS number
131-13-5
InChI Key
GZBACHSOZNEZOG-UHFFFAOYSA-J
InChI
InChI=1S/C11H12O8P2.4Na/c1-7-6-10(18-20(12,13)14)8-4-2-3-5-9(8)11(7)19-21(15,16)17;;;;/h2-6H,1H3,(H2,12,13,14)(H2,15,16,17);;;;/q;4*+1/p-4
IUPAC Name
tetrasodium 3-methyl-4-(phosphonatooxy)naphthalen-1-yl phosphate
SMILES
[Na+].[Na+].[Na+].[Na+].CC1=C(OP([O-])([O-])=O)C2=CC=CC=C2C(OP([O-])([O-])=O)=C1

References

General References
  1. Criddle DN, Gillies S, Baumgartner-Wilson HK, Jaffar M, Chinje EC, Passmore S, Chvanov M, Barrow S, Gerasimenko OV, Tepikin AV, Sutton R, Petersen OH: Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J Biol Chem. 2006 Dec 29;281(52):40485-92. doi: 10.1074/jbc.M607704200. Epub 2006 Nov 6. [Article]
  2. Gong X, Gutala R, Jaiswal AK: Quinone oxidoreductases and vitamin K metabolism. Vitam Horm. 2008;78:85-101. doi: 10.1016/S0083-6729(07)00005-2. [Article]
  3. Kappadione patent [Link]
  4. Endocrine Disrupters [Link]
  5. Vitamin K, Systemic [Link]
  6. Menadiol Sodium [Link]
  7. Menadiol Sodium Pharmacology [Link]
  8. Foye's Principles of Medicinal Chemistry [Link]
  9. Drugs and haemostats [Link]
  10. Menadiol [Link]
  11. Menadiol diphosphate, a new substrate for non-specific alkaline phosphatase in histochemistry and immunohistochemistry [Link]
  12. Vitamin K metabolism [Link]
  13. A pharmacokinetic study with the high-dose anticancer agent menadione in rabbits [Link]
  14. Chapter 10. Vitamin K [Link]
  15. Menadione [Link]
PubChem Compound
8555
PubChem Substance
310265211
ChemSpider
8237
Wikipedia
Kappadione

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
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Not AvailableCompletedBasic SciencePharmacokinetics1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)655.30http://www.thegoodscentscompany.com/data/rw1609581.html
Predicted Properties
PropertyValueSource
Water Solubility8.03 mg/mLALOGPS
logP2.37ALOGPS
logP1.56Chemaxon
logS-1.7ALOGPS
pKa (Strongest Acidic)1.47Chemaxon
Physiological Charge-4Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area144.84 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity68.77 m3·mol-1Chemaxon
Polarizability26.13 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-00di-0000900000-59644df48a55a6752857
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-178.189705
predicted
DarkChem Lite v0.1.0
[M-H]-148.24687
predicted
DeepCCS 1.0 (2019)
[M+H]+150.64897
predicted
DeepCCS 1.0 (2019)
[M+Na]+156.55495
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Prothrombin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. Thrombin triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL8/CXCL8, in endothelial cells (PubMed:30568593, PubMed:9780208)
Specific Function
Calcium ion binding
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
Details2. Coagulation factor VII
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium
Specific Function
Calcium ion binding
Gene Name
F7
Uniprot ID
P08709
Uniprot Name
Coagulation factor VII
Molecular Weight
51593.465 Da
References
  1. Menadiol Sodium Pharmacology [Link]
Details3. Coagulation factor IX
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa
Specific Function
Calcium ion binding
Gene Name
F9
Uniprot ID
P00740
Uniprot Name
Coagulation factor IX
Molecular Weight
51778.11 Da
References
  1. Menadiol Sodium Pharmacology [Link]
Details4. Coagulation factor X
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. Factor Xa activates pro-inflammatory signaling pathways in a protease-activated receptor (PAR)-dependent manner (PubMed:24041930, PubMed:30568593, PubMed:34831181). Up-regulates expression of protease-activated receptors (PARs) F2R, F2RL1 and F2RL2 in dermal microvascular endothelial cells (PubMed:35738824). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL6, in cardiac fibroblasts and umbilical vein endothelial cells in PAR-1 (F2R)-dependent manner (PubMed:30568593, PubMed:34831181). Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2, IL6, TNF-alpha/TNF, IL-1beta/IL1B, IL8/CXCL8 and IL18, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Induces expression of adhesion molecules, such as ICAM1, VCAM1 and SELE, in endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824, PubMed:9780208). Increases expression of phosphorylated ERK1/2 in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Triggers activation of the transcription factor NF-kappa-B in dermal microvascular endothelial cells and atrial tissues (PubMed:24041930, PubMed:35738824). Up-regulates expression of plasminogen activator inhibitor 1 (SERPINE1) in atrial tissues (PubMed:24041930)
Specific Function
Calcium ion binding
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Menadiol Sodium Pharmacology [Link]
Details5. Vitamin K-dependent protein C
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts a protective effect on the endothelial cell barrier function (PubMed:25651845)
Specific Function
Calcium ion binding
Gene Name
PROC
Uniprot ID
P04070
Uniprot Name
Vitamin K-dependent protein C
Molecular Weight
52070.82 Da
References
  1. Menadiol Sodium Pharmacology [Link]
Details6. Vitamin K-dependent gamma-carboxylase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide (PubMed:17073445). Catalyzes gamma-carboxylation of various proteins, such as blood coagulation factors (F2, F7, F9 and F10), osteocalcin (BGLAP) or matrix Gla protein (MGP) (PubMed:17073445)
Specific Function
Gamma-glutamyl carboxylase activity
Gene Name
GGCX
Uniprot ID
P38435
Uniprot Name
Vitamin K-dependent gamma-carboxylase
Molecular Weight
87560.065 Da
References
  1. Menadiol Sodium Pharmacology [Link]
Details7. Vitamin K-dependent protein S
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis
Specific Function
Calcium ion binding
Gene Name
PROS1
Uniprot ID
P07225
Uniprot Name
Vitamin K-dependent protein S
Molecular Weight
75121.905 Da
References
  1. Menadiol Sodium Pharmacology [Link]

Enzymes

Details1. Vitamin K epoxide reductase complex subunit 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development
Specific Function
Quinone binding
Gene Name
VKORC1
Uniprot ID
Q9BQB6
Uniprot Name
Vitamin K epoxide reductase complex subunit 1
Molecular Weight
18234.3 Da
References
  1. Vitamin K metabolism [Link]
Details2. NADPH--cytochrome P450 reductase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5
Specific Function
Flavin adenine dinucleotide binding
Gene Name
POR
Uniprot ID
P16435
Uniprot Name
NADPH--cytochrome P450 reductase
Molecular Weight
76689.12 Da
References
  1. Menadiol Sodium Pharmacology [Link]

Drug created at November 24, 2015 19:24 / Updated at March 08, 2024 01:21