Vitamin K1, or phylloquinone, is a prenylated naphthoquinone that is only produced by plants, green algae, and certain cyanobacteria species. In photosystem I, it plays a crucial role as an electron transporter, and it also acts as an electron acceptor to facilitate the creation of protein disulfide bonds. Phylloquinone functions as vitamin K1, a vitamin necessary for blood coagulation, bone and vascular metabolism, in humans and other vertebrates. Green leafy vegetables and vegetable oil, which contain phylloquinone, are the main dietary sources of vitamin K for humans[1]. With the help of the MAPK pathway, vitamin K1 therapy significantly reduces proliferation and triggers apoptosis in the Caco-2, HT-29, and SW480 cell lines. There is a concurrent, notable decline in the production of polyamines [2].

Compared to participants who decreased or did not alter their phylloquinone consumption, those who increased their dietary intake of vitamin K during the follow-up had a 51% lower incidence of incident diabetes[3]. By regulating osteoblast and osteoclast activity and preventing bone loss in obese mice produced by a high-fat diet, vitamin K treatment reverses the effects of a high-fat diet on bone deterioration[4]. Vitamin K1 has been applied topically to the skin to reduce pigmentation and heal bruises. When compared to the control group, the topical vitamin K1 effects demonstrate considerable healing in metrics such wound contraction, epithelialization period, hydroxyproline content, and tensile strength[5].

Absorption, Distribution and Excretion
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.
Intravenous phylloquinone is 36% eliminated in the feces in 5 days and 22% recovered in urine in 3 days.
The steady state volume of distribution of phylloquinone is 20 ± 6 L in subjects who are also taking phenprocoumon therapy.
Intravenous phylloquinone is 90% cleared in 2 hours, and 99% cleared in 8 hours. A 10 mg intravenous dose of phylloquinone has a mean clearance of 91 ± 24 mL/min.
Little is known about the excretion of vitamin K. High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.
Although the drug may be concentrated in the liver for a short time after absorption, only small amounts of phytonadione are stored in body tissues.
Phytonadione is absorbed from the GI tract only in the presence of bile salts. Radioisotope studies show that absorption occurs via intestinal lymph. There is some evidence that absorption of phytonadione across the GI mucosa is a saturable, energy-dependent process that occurs in the proximal small intestine.
Fat-soluble vit...k...absorbed from skin... /vit k/
For more Absorption, Distribution and Excretion (Complete) data for PHYTONADIONE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
...In experimental animals...phylloquinone...can be converted to more potent menaquinone series. Whether this can occur in man and of what significance these transformations are to action of phylloquinone...are still unknown.
In animals treated with warfarin, major fraction of phylloquinone is metabolized to phylloquinone oxide.
Phytonadione is rapidly metabolized to more polar metabolites, which are excreted in the bile and urine. The major urinary metabolites result from shortening of the side chain to five or seven carbon atoms, yielding carboxylic acids that are conjugated with glucuronate prior to excretion. Treatment with a coumarin-type anticoagulant results in a marked increase in the amount of phytonadione-2,3-epoxide in the liver and blood. Such treatment also increases the urinary excretion of phytonadione metabolites, primarily degradative products of phytonadione-2,3-epoxide. The biliary metabolites of phytonadione have not been identified.
The liver plays an exclusive role in the metabolic transformations leading to the elimination of vitamin K from the body. After intravenous doses of 45 ug to 1 mg (3)H-phylloquinone, about 20% of the radiolabel was excreted in the urine within three days, and 35-50% was excreted as metabolites in the feces via the bile.

Route of Elimination: Almost no free unmetabolized vitamin K appears in bile or urine.

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Biological Half-Life
Intravenous phylloquinone has an initial half life of 22 minutes, followed by a half life of 125 minutes.

Toxicity Summary
Vitamin K is an essential cofactor for the gamma-carboxylase enzymes which catalyze the posttranslational gamma-carboxylation of glutamic acid residues in inactive hepatic precursors of coagulation factors II (prothrombin), VII, IX and X. Gamma-carboxylation converts these inactive precursors into active coagulation factors which are secreted by hepatocytes into the blood. Supplementing with Phylloquinone results in a relief of vitamin K deficiency symptoms which include easy bruisability, epistaxis, gastrointestinal bleeding, menorrhagia and hematuria.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Vitamin K is naturally found in human milk. Maternal vitamin K supplementation is typically not needed to meet the 75 mcg per day recommended adequate maternal dietary intake during lactation. Maternal supplementation with 5 mg daily increases milk vitamin K levels and can improve vitamin K status in breastfed infants who also receive intramuscular vitamin K shortly after birth. Although exclusively breastfed infants are at higher risk of vitamin K deficiency bleeding (VKDB), a condition that can involve intracranial hemorrhage, sometimes leading to infant death, maternal vitamin K supplementation alone is not an adequate or safe substitute for vitamin K administered directly to the newborn after birth to prevent VKDB, especially in preterm infants.
◉ Effects in Breastfed Infants
Exclusive breastfeeding and failure to give infants a dose of prophylactic vitamin K at birth resulted in the death of 3 otherwise normal, consecutive male siblings from intracranial hemorrhage. A fourth male sibling was examined at 17 days of age and found to have abnormal clotting parameters. The infant and parents were found to have no genetic conditions that could account for the abnormal clotting. Within 24 hours, the infant’s clotting profile normalized after 1 mg of vitamin K injection.

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Toxicity Data
LD50: 41.5 mL/kg at 0.2% (Intravenous, Mouse) (A308)
LD50: 52 mL/kg at 1% (Intravenous, Mouse) (A308)

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Interactions
Vit k antagonizes inhibitory effect of /acenocoumarol, phenprocoumon, anisindione, diphenadione, & phenindione/ on hepatic synthesis of vit k-dependent clotting proteins... /vit k/
Requirements for vitamin K may be increased in patients receiving /broad-spectrum antibiotics, moxalactam, quinidine, quinine, high doses of salicylates, or antibacterial sulfonamides/.
Concurrent use /with dactinomycin/ may decrease the effects of vitamin K; evidence is inconclusive, observation of patients is recommended and a higher dose of vitamin K may be required. /Vitamin K/
Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with vitamin K may decrease the effects of these anticoagulants as a result of increased hepatic synthesis of procoagulant factors. When reinstituting oral anticoagulant therapy after the administration of large doses of vitamin K, it may be necessary to temporarily increase the dose of the oral anticoagulant, or to use one such as heparin that acts on a different principle. /Vitamin K/
For more Interactions (Complete) data for PHYTONADIONE (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse oral 25 g/kg
LD50 Mouse subcutaneous 1000 mg/kg

[1]. Basset GJ, et al. Phylloquinone (Vitamin K1): Occurrence, Biosynthesis and Functions. Mini Rev Med Chem. 2016 Jun 22.
[2]. Orlando A, et al. Vitamin K1 exerts antiproliferative effects and induces apoptosis in three differently graded human colon cancer cell lines. Biomed Res Int. 2015;2015:296721.
[3]. Ibarrola-Jurado N, et al. Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease. Am J Clin Nutr. 2012 Nov;96(5):1113-8.
[4]. Kim M, et al. Vitamin K1 (phylloquinone) and K2 (menaquinone-4) supplementation improves bone formation in a high-fat diet-induced obese mice. J Clin Biochem Nutr. 2013 Sep;53(2):108-13.
[5]. Hemmati AA, et al. Topical vitamin K1 promotes repair of full thickness wound in rat. Indian J Pharmacol. 2014 Jul-Aug;46(4):409-12

Therapeutic Uses
Antifibrinolytic Agents
THE RATIONAL THERAPEUTIC USE OF VITAMIN K IS BASED ON ITS ABILITY TO CORRECT BLEEDING TENDENCY OR HEMORRHAGE ASSOC WITH ITS DEFICIENCY. A DEFICIENCY OF VITAMIN K & ITS ATTENDANT DEFICIENCY OF PROTHROMBIN & RELATED CLOTTING FACTORS CAN RESULT FROM INADEQUATE INTAKE, ABSORPTION, OR UTILIZATION OF VITAMIN, OR AS A CONSEQUENCE OF ACTION OF THE ACTION OF A VITAMIN K ANTAGONIST. /VITAMIN K/
BLEEDING THAT ACCOMPANIES OBSTRUCTIVE JAUNDICE OR BILIARY FISTULA RESPONDS PROMPTLY TO ADMINISTRATION OF VITAMIN K. ORAL PHYTONADIONE ADMIN WITH BILE SALTS IS BOTH SAFE AND EFFECTIVE AND SHOULD BE USED IN THE CARE OF THE JAUNDICED PATIENT, BOTH PREOPERATIVELY & POSTOPERATIVELY.
IF FOR SOME REASON ORAL ADMIN IS NOT FEASIBLE /IN TREATMENT OF OBSTRUCTIVE JAUNDICE OR BILIARY FISTULA/, A PARENTERAL PREPN SHOULD BE USED.
For more Therapeutic Uses (Complete) data for PHYTONADIONE (22 total), please visit the HSDB record page.

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Drug Warnings
IN PT WHO HAVE SEVERE HEPATIC DISEASE, ADMIN OF LARGE DOSES OF MENADIONE OR PHYLLOQUINONE MAY FURTHER DEPRESS FUNCTION OF LIVER.
Maternal Medication usually Compatible with Breast-Feeding: K1 (vitamin): Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/
A rare hypersensitivity-like reaction, which has occasionally resulted in death, has been reported after intravenous administration of phytonadione, especially when administration is rapid.
In newborns, especially premature infants, mendiol sodium diphosphate has been associated with hemolytic anemia, hyperbilirubinemia, and kernicterus because of immature hepatic function in these infants. There is less risk with phytonadione, unless high doses are given.
For more Drug Warnings (Complete) data for PHYTONADIONE (21 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C31H46O2

450.6957

450.349

84-80-0

5284607

Yellow viscous oil
LIGHT-YELLOW SOLIDS OR OILS
Pale yellow oil or yellow crystals
Clear, yellow to amber, viscous, odourless liquid

1.0±0.1 g/cm3

546.4±50.0 °C at 760 mmHg

−20 °C(lit.)

200.4±27.1 °C

0.0±1.5 mmHg at 25°C

1.511

12.25

0

2

14

33

696

2

O=C1C(C/C=C(\C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2C=CC=CC1=2

MBWXNTAXLNYFJB-NKFFZRIASA-N

InChI=1S/C31H46O2/c1-22(2)12-9-13-23(3)14-10-15-24(4)16-11-17-25(5)20-21-27-26(6)30(32)28-18-7-8-19-29(28)31(27)33/h7-8,18-20,22-24H,9-17,21H2,1-6H3/b25-20+/t23-,24-/m1/s1

2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione

Phylloquinone; Phytomenadione; VITAMIN K1; Phylloquinone; 3-Phytylmenadione; Alpha-Phylloquinone; Aquamephyton, Konakion, Phyllohydroquinone, Phytomenadione, Phytonadione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol :≥ 50 mg/mL (~110.94 mM)
DMSO : ~5.6 mg/mL (~12.43 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.55 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 20 mg/mL (44.38 mM) in Cremophor EL (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)