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Kappadione | CAS No: 131-13-5 | GMP-certified suppliers
A medication that treats and prevents vitamin K deficiency-related bleeding disorders from anticoagulant therapy, newborn hemorrhagic disease, and malabsorption conditions affecting coagulation.
Primary indications
- 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) [L1545, L1546]
Product Snapshot
- Kappadione is an oral small molecule formulation
- It is used primarily for treatment and prophylaxis of vitamin K deficiency-related coagulopathies, including anticoagulant-induced prothrombin deficiency and hemorrhagic disease of the newborn
- Kappadione holds regulatory approval for indicated uses
Clinical Overview
Clinically, Kappadione has been indicated for the treatment and prevention of hypoprothrombinemia caused by anticoagulant therapies such as coumadin or indanedione derivatives, as well as hemorrhagic disease of the newborn. It is utilized in states of vitamin K deficiency secondary to impaired absorption or synthesis, including obstructive jaundice, biliary fistula, intestinal diseases (such as sprue, ulcerative colitis, celiac disease), pancreatic cystic fibrosis, and other drug-induced coagulopathies proven to interfere with vitamin K metabolism.
Pharmacodynamically, Kappadione functions by restoring adequate levels of vitamin K necessary for the hepatic synthesis and posttranslational modification of vitamin K-dependent clotting factors II (prothrombin), VII, IX, and X. The mechanism of action involves its role as a cofactor in the gamma-carboxylation of glutamic acid residues on these factors, a critical step for coagulation cascade functionality. The active reduced form, vitamin K hydroquinone, serves as the direct cofactor for gamma-glutamyl carboxylase enzymes. Additionally, vitamin K-dependent proteins involved in bone metabolism, such as osteocalcin and matrix Gla protein, are also gamma-carboxylated in this process.
Absorption, distribution, metabolism, and excretion parameters specific to menadiol sodium diphosphate are limited. However, as a water-soluble analog, it exhibits enhanced solubility relative to lipid-soluble vitamin K forms, potentially altering pharmacokinetics and bioavailability.
Safety concerns include documented cytotoxicity and carcinogenic potential observed in mammalian cell studies. Furthermore, toxicity associated with the metabolite menadione includes reproductive toxicity, with oocyte damage noted in animal models. These factors have contributed to the discontinuation and restricted clinical use of this compound in several regions.
Given its chemical classification as a naphthalene derivative, handling and storage protocols should consider potential toxicity and stability characteristics typical of such compounds. API procurement requires stringent quality control to ensure absence of toxic impurities and consistent pharmacological activity. Suppliers must comply with regulatory standards pertinent to vitamin K analogs, including thorough documentation of origin, synthesis, and analytical validation.
Identification & chemistry
| Generic name | Kappadione |
|---|---|
| Molecule type | Small molecule |
| CAS | 131-13-5 |
| UNII | R2L46WE615 |
| DrugBank ID | DB09332 |
Pharmacology
| Summary | Menadiol sodium phosphate (vitamin K3) acts as a cofactor for vitamin K-dependent gamma-carboxylases, catalyzing the posttranslational gamma-carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X, as well as proteins C and S, which are essential for blood coagulation. This process facilitates activation of the clotting cascade, thereby supporting hemostasis. The compound is primarily utilized to correct vitamin K deficiency-related coagulopathies resulting from impaired synthesis or absorption of vitamin K. |
|---|---|
| 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 . |
| 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 . |
Targets
| Target | Organism | Actions |
|---|---|---|
| Prothrombin | Humans | agonist |
| Coagulation factor VII | Humans | agonist |
| Coagulation factor IX | Humans | agonist |
ADME / PK
| 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 . |
|---|---|
| Half-life | Mean elimination half-life of menadione was 27.17 min in the plasma of rabbits, in one study . |
| 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 . 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 . |
| 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 . 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 . |
| Volume of distribution | In a study of rabbits, the apparent volume of distribution (V(d)/F) in plasma was 30.833 ± 12.835 L . |
| Clearance | The plasma clearance (CL/F) of VK3 was 0.822 ± 0.254 L min-1. |
Formulation & handling
- Kappadione is a small molecule with moderate lipophilicity suitable for oral formulation development. Its solid state and water solubility of approximately 8 g/L support aqueous formulation and standard handling procedures. As a naphthalene derivative, stability under light and oxidative conditions should be evaluated during formulation.
Regulatory status
Safety
| Toxicity | This medication has been associated with increased risk of kernicterus and hemolytic anemia in premature infants . 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 . |
|---|
- Avoid use in premature infants and individuals with G6PD deficiency due to risk of hemolytic anemia and free radical-induced liver damage
- Handle with care to prevent exposure, as the compound may contribute to oxidative stress mechanisms
- Monitor for potential hematologic toxicity in populations susceptible to vitamin K metabolism interference
Kappadione is a type of Anticoagulant proteins
Anticoagulant proteins are a crucial subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a vital role in preventing the formation of blood clots. These proteins are naturally occurring substances that interfere with the clotting cascade, a complex series of reactions that lead to blood coagulation.
One of the well-known anticoagulant proteins is hirudin, derived from leeches. Hirudin acts by inhibiting thrombin, a key enzyme involved in blood clot formation. Another notable anticoagulant protein is antithrombin III, which blocks several clotting factors, including thrombin and factors IXa, Xa, XIa, and XIIa. These proteins are widely used in the pharmaceutical industry to develop medications for conditions such as deep vein thrombosis, pulmonary embolism, and stroke prevention.
The production of anticoagulant proteins involves advanced biotechnological processes. Recombinant DNA technology and genetic engineering techniques are employed to produce these proteins in large quantities. The proteins are expressed in host organisms such as bacteria, yeast, or mammalian cells, and then purified through various chromatographic and filtration steps to obtain a highly pure and active form.
The development of anticoagulant proteins has significantly improved the treatment and management of thrombotic disorders. These APIs have proven to be effective in preventing clot formation, reducing the risk of life-threatening complications. However, it is crucial to administer anticoagulant proteins under medical supervision due to their potential side effects and the need for precise dosing.
In conclusion, anticoagulant proteins are a vital subcategory of pharmaceutical APIs that act by inhibiting key components of the clotting cascade. Their production involves advanced biotechnological processes, and they have greatly enhanced the management of thrombotic disorders. Proper medical guidance is essential for their safe and effective use.
Kappadione (Anticoagulant proteins), classified under Anticoagulants
Anticoagulants are a vital category of pharmaceutical active pharmaceutical ingredients (APIs) used to prevent and treat blood clotting disorders. These medications play a crucial role in various medical conditions, including deep vein thrombosis (DVT), pulmonary embolism (PE), and atrial fibrillation (AF). Anticoagulants work by inhibiting the formation of blood clots or by preventing existing clots from getting larger.
There are different types of anticoagulants available, including direct thrombin inhibitors, vitamin K antagonists, and factor Xa inhibitors. Direct thrombin inhibitors, such as dabigatran, directly target the enzyme thrombin to hinder clot formation. Vitamin K antagonists, like warfarin, interfere with the production of clotting factors that rely on vitamin K. Factor Xa inhibitors, such as rivaroxaban and apixaban, inhibit the activity of factor Xa, a crucial component in the clotting cascade.
Anticoagulants are commonly prescribed to patients at risk of developing blood clots or those with existing clotting disorders. They are often used during surgeries, such as hip or knee replacements, to minimize the risk of post-operative clot formation. Patients with AF, a condition characterized by irregular heart rhythm, may also be prescribed anticoagulants to prevent stroke caused by blood clots.
While anticoagulants offer significant benefits in preventing and treating clot-related conditions, they also carry potential risks, including bleeding complications. Patients taking anticoagulants require careful monitoring to ensure the right dosage is administered, as excessive anticoagulation can lead to hemorrhage. Regular blood tests and close medical supervision are essential to manage the delicate balance between preventing clots and avoiding excessive bleeding.
In conclusion, anticoagulants are a crucial category of pharmaceutical APIs used to prevent and treat blood clotting disorders. They function by inhibiting clot formation or preventing existing clots from enlarging. While highly beneficial, their use requires careful monitoring to minimize the risk of bleeding complications.
Kappadione API manufacturers & distributors
Compare qualified Kappadione API suppliers worldwide. We currently have 1 companies offering Kappadione API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Chemspec-API | Producer | United States | Unknown | CoA, USDMF | 3 products |
When sending a request, specify which Kappadione API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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