Vitamin K1

Description

Vitamin K₁ is a fat-soluble, dietary nutrient that is essential for the synthesis of proteins important for blood-clotting, bone metabolism, and cell growth. It is found in the photosynthetic tissues of green, leafy plants, where it acts as an electron acceptor forming part of the electron transport chain of Photosystem I. Vitamin K₁ also serves as a precursor to vitamin K₂ and is reported to exhibit anticancer activity in various cell lines.

Chemical properties

Yellow Oil

Chemical properties

Phylloquinone is an odorless yellow viscous oil or crystals.

Originator

Mephyton ,MSD ,US ,1941

The Uses of Vitamin K1

Vitamin K1 is a fat-soluble, dietary nutrient that is essential for the synthesis of proteins important for blood-clotting, bone metabolism, and cell growth.

The Uses of Vitamin K1

Occurs widely in green plants, algae, photosynthetic bacteria.

The Uses of Vitamin K1

Labeled Phytonadione, intended for use as an internal standard for the quantification of Phytonadione by GC- or LC-mass spectrometry.

Indications

Oral phylloquinone is indicated to treat prothrombin deficiency caused by coumarin or indanedione derivatives; and hypoprothrombinemia secondary to antibacterial therapy, salicylates, or obstructive jaundice or biliary fistulas with concomitant bile salt administration.
Parenteral (intravenous, intramuscular, and subcutaneous) phylloquinone is indicated to treat coagulation disorders due to faulty formation of coagulation factors II, VII, IX, and X caused by vitamin K deficiency or some interference with vitamin K activity. These indications include the above indications as well as hypoprothrombinemia secondary to sprue, ulcerative colitis, celiac disease, intestinal resection, pancreatic cystic fibrosis, or regional enteritis; or hypoprothrombinemia caused by interference with vitamin k metabolism.

Background

Vitamin K1, also called phylloquinone or phytonadione, is a fat soluble vitamin. Phylloquinone is a cofactor of the enzyme γ-carboxylase, which modifies and activates precursors to coagulation factors II, VII, IX, and X. It is indicated in the treatment of coagulation disorders due to faulty formation of coagulation factors II, VII, IX, and X caused by deficiency or interference in the activity of vitamin K.
Phylloquinone has been synthesized since at least 1939, and was approved by the FDA prior to 1955.

Definition

ChEBI: Phylloquinone is a member of the class of phylloquinones that consists of 1,4-naphthoquinone having methyl and phytyl groups at positions 2 and 3 respectively. The parent of the class of phylloquinones. It has a role as a cofactor, a plant metabolite and a human metabolite. It is a vitamin K and a member of phylloquinones.

Manufacturing Process

11 parts by weight of 2-methyl-1,4-naphthohydroquinone, 30 parts by volume of water-free dioxane and 1.5 parts by volume of boron trifluoride etherate are heated to 50°C. While agitating and introducing nitrogen, 10 parts by weight of phytol dissolved in 10 parts by volume of dioxane are added in the course of 15 minutes. Thereupon, the dark colored reaction mixture is stirred for 20 additional minutes at 50°C, cooled down and 60 parts by volume of ether are added. The reaction mixture is washed first with water, then with a mixture of 3 parts of N-sodium hydroxide and 2 parts of a 2.5% solution of sodium hydrosulfite and again with water. The aqueous extracts are washed with ether. The ether solutions are collected, dried over sodium sulfate and concentrated, toward the end under reduced pressure.
The waxlike condensation product so obtained is mixed with 60 parts by volume of petroleum ether (boiling limits 30°C to 40°C) and agitated with hydrogen in the presence of a little active palladium lead catalyst (Pd-CaCO3catalyst, the activity of which is reduced by the addition of lead and quinoline). During the operation, the condensation product separates in the form of a voluminous white precipitate. The latter is separated by filtration in the absence of air while adding an inert coarse-grained adsorption agent (for example, aluminum silicate salt for filter purposes), and washed with cooled petroleum ether. Thereupon, the 2-methyl-3-phytyl-1,4-naphthohydroquinone is extracted from the filter cake by means of ether, the ethereal solution is concentrated to 100 parts by volume and the reaction product is oxidized by stirring the solution with 6.6 parts by weight of silver oxide during 30 minutes. The solution is filtered through sodium sulfate, the latter is rinsed with ether and the solvent is evaporated. There are obtained 5.7 parts by weight of 2-methyl-3-phytyl-1,4-naphthoquinone (vitamin K1) in the form of a golden yellow oil.

Therapeutic Function

Prothrombogenic vitamin

General Description

Vitamin K₁, also known as phylloquinone, consists of naphthalenoid and phytyl groups. Phylloquinone is present abundantly in photosynthetic plants and is a major dietary source. It is a fat-soluble vitamin.

Biochem/physiol Actions

Vitamin K1 (Phylloquinone) is a lipid soluble polycyclic aromatic ketone used as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX and X; anticoagulant factors protein C and S and as a cell signaling factor. Vitamin K1 is essential for blood coagulation, bone and vascular metabolism. Phylloquinone from green leafy vegetables and vegetable oil is the most important dietary source of vitamin K for humans.

Pharmacokinetics

Phylloquinone is a vitamin K indicated in the treatment of coagulation disorders due to faulty formation of coagulation factors II, VII, IX, and X caused by deficiency or interference in the activity of vitamin K. It has a long duration of action as vitamin K is cycled in the body, and a wide therapeutic index as large doses can be tolerated. Patients should have their prothrombin time monitored during therapy and healthcare professionals should be aware of the increased risk of hypersensitivity reactions with parenteral administration.

Clinical Use

Vitamin K deficiency
Antidote to oral anticoagulants

Potential Exposure

Phylloquinone is a dietary component essential for normal biosynthesis of several factors required for clotting of blood; as a therapeutic drug used to correct bleeding tendency; and as a food supplement.

Veterinary Drugs and Treatments

The principal uses of exogenously administered phytonadione is in the treatment of anticoagulant rodenticide toxicity. It is also used for treating dicumarol toxicity associated with sweet clover ingestion in ruminants, sulfaquinoxaline toxicity, and in bleeding disorders associated with faulty formation of vitamin K-dependent coagulation factors.

Drug interactions

Potentially hazardous interactions with other drugs
Antagonises effect of coumarins and phenindione.

Absorption

A 4 μg oral dose of phylloquinone is 13% ± 9% bioavailable, with a Tmax of 4.7 ± 0.8 hours. 1.5 ± 0.8 nmol is found in the plasma compartment, and 3.6 ± 3.4 nmol is found in the second compartment.
A 10 mg intramuscular phylloquinone dose is 89.2% ± 25.4% bioavailable. The same dose reaches a mean Cmax of 67 ± 30 ng/mL, with a mean Tmax of 9.2 ± 6.6 hours, and an AUC of 1700 ± 500 h*ng/mL.
A 10 mg intravenous phylloquinone dose has a mean AUC of 1950 ± 450 h*ng/mL.

Metabolism

Phylloquinone's phytyl side chain is omega hydroxylated by CYP4F2. The side chain is then cleaved to 5 or 7 carbons long, and then glucuronidated prior to elimination.
Vitamin Ks in general undergo a cycle of reduction to vitamin K hydroquinone by vitamin K epoxide reductase (VKOR), oxidation to vitamin K epoxide by gamma-glutamyl carboxylase, and converted back to vitamin K by VKOR.

Metabolism

Phytomenadione is rapidly metabolised to more polar metabolites and is excreted in bile and urine as glucuronide and sulphate conjugates.

Toxicity

High doses of vitamin K1 are not associated with toxicity. Intravenous administration has been associated with an increased risk of toxicity. These patients should be treated with symptomatic and supportive measures.
The intravenous LD50 in mice is 1170 mg/kg and the oral LD50 is >24180 mg/kg.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

Vitamin K1 is a yellow viscous oil, which can be distilled at high vacuum practically unchanged. It is insoluble in H2O, but soluble in common organic solvents. Store it in the dark under N2 as it is oxygen sensitive. It has  1cm 328 at 248nm. [Fieser et al. J Am Chem Soc 61 2557 1939, Hirschmann et al. J Am Chem Soc 76 4592 1954, Isler & Doebel Helv Chim Acta 27 225 1954, Beilstein 7 IV 2496.]

Incompatibilities

Phylloquinone is photosensitive; decomposes in sunlight and is destroyed by alkali hydroxides and reducing agents such as hydrideds and active metals. Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.