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
The bioavailability of 4 µg phylloquinone orally was 13% ± 9%, with a time to peak concentration (Tmax) of 4.7 ± 0.8 hours. The plasma concentration of phylloquinone was 1.5 ± 0.8 nmol, and the concentration in the second chamber was 3.6 ± 3.4 nmol. The bioavailability of 10 mg phylloquinone intramuscularly was 89.2% ± 25.4%. At the same dose, the mean peak plasma concentration (Cmax) was 67 ± 30 ng/mL, the mean time to peak concentration (Tmax) was 9.2 ± 6.6 hours, and the area under the curve (AUC) was 1700 ± 500 hng/mL. The mean AUC of 10 mg phylloquinone intravenously was 1950 ± 450 hng/mL.
36% of intravenously administered phylloquinone was excreted in feces within 5 days and 22% in urine within 3 days.
In subjects concurrently receiving phenylcoumarin, the steady-state volume of distribution of phylloquinone was 20 ± 6 liters.
90% of intravenously administered phylloquinone was cleared within 2 hours and 99% within 8 hours. The mean clearance of 10 mg of intravenously administered phylloquinone was 91 ± 24 mL/min.
Little is known about vitamin K excretion. High concentrations of vitamin K in feces are likely due to synthesis by intestinal bacteria.
Although the drug may be transiently concentrated in the liver after absorption, only small amounts of phytomenadione are stored in the body's tissues.
Phytomenadione can only be absorbed from the gastrointestinal tract in the presence of bile acids. Radioisotope studies indicate that its absorption route is the intestinal lymphatic system. There is evidence that the absorption of phytomenadione via the gastrointestinal mucosa is a saturable, energy-dependent process occurring in the proximal small intestine.
Fat-soluble vitamin K…absorbed through the skin…/Vitamin K/
For more complete data on the absorption, distribution, and excretion of phytoquinones (7 in total), please visit the HSDB record page.

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Metabolism/Metabolites
The phyto-based side chain of phylloquinone is ω-hydroxylated by CYP4F2. The side chain is then cleaved into 5 or 7 carbon atoms and then glucuronidated before elimination. Vitamin K typically undergoes a cycle: first, it is reduced to vitamin K hydroquinone by vitamin K epoxide reductase (VKOR), then oxidized to vitamin K epoxide by γ-glutamyl carboxylase, and finally reduced back to vitamin K by VKOR.
…In experimental animals…phylloquinone…can be converted into the more active menadione family of compounds. Whether this conversion occurs in humans, and what significance these conversions have for the effects of phylloquinone…is currently unknown.
In animals treated with warfarin, most phylloquinone is metabolized to phylloquinone oxide.
Phytoquinone is rapidly metabolized into more polar metabolites, which are excreted via bile and urine. The main urinary metabolites are produced by the shortening of the side chain to five or seven carbon atoms, generating carboxylic acids, which bind to glucuronic acid before excretion. Treatment with coumarin anticoagulants leads to a significant increase in the levels of phytoquinone-2,3-epoxide in the liver and blood. Such treatment also increases the excretion of phytoquinone metabolites in urine, which are mainly degradation products of phytoquinone-2,3-epoxide. Bile metabolites of phytoquinone have not yet been identified.
The liver plays a unique role in the metabolic transformation of vitamin K for removal from the body. Following intravenous injection of 45 μg to 1 mg (3)H-chloroquinone, approximately 20% of the radiolabeled material is excreted in urine within three days, and 35–50% is excreted in feces via bile as metabolites. Elimination pathway: Almost no free, unmetabolized vitamin K is found in bile or urine. Biological half-life: The initial half-life of intravenously administered phylloquinone is 22 minutes, followed by a half-life of 125 minutes.

Toxicity Summary
Vitamin K is an essential cofactor for γ-carboxylase, which catalyzes the post-translational γ-carboxylation of glutamate residues in inactive hepatic precursors of coagulation factors II (prothrombin), VII, IX, and X. γ-carboxylation converts these inactive precursors into active coagulation factors, which are then secreted into the bloodstream by hepatocytes. Phloroquinone supplementation can alleviate vitamin K deficiency symptoms, including easy bruising, nosebleeds, gastrointestinal bleeding, menorrhagia, and hematuria. Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation Vitamin K is naturally present in breast milk. Lactating women typically do not require additional vitamin K supplementation to meet the recommended daily intake of 75 micrograms. Daily maternal supplementation with 5 mg of vitamin K can increase vitamin K levels in breast milk and improve vitamin K status in breastfed infants who receive intramuscular vitamin K injections shortly after birth. While exclusively breastfed infants have a higher risk of vitamin K deficiency bleeding (VKDB), which can cause intracranial hemorrhage and sometimes even infant death, maternal vitamin K supplementation alone is not a sufficient or safe alternative to postnatal vitamin K supplementation for preventing VKDB, especially in premature infants.
◉ Impact on Breastfed Infants
Exclusive breastfeeding without prophylactic vitamin K administration at birth resulted in the deaths of three previously healthy male siblings from intracranial hemorrhage. A fourth male sibling was found to have abnormal coagulation function 17 days after birth. Further examination revealed no genetic diseases in the infant or his parents that could cause coagulation abnormalities. After an injection of 1 mg of vitamin K, the infant's coagulation function returned to normal within 24 hours.

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Toxicity Data
LD50: 41.5 mL/kg (intravenous injection, mice) at 0.2% concentration (A308)
LD50: 52 mL/kg (intravenous injection, mice) at 1% concentration (A308)

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Interactions
Vitamin K antagonism/acetocoumarin, phenylpropromin, anisole, benzophenone, and phenylindone/inhibition of hepatic synthesis of vitamin K-dependent clotting proteins…/Vitamin K/
Patients receiving/broad-spectrum antibiotics, mosaltan, quinidine, quinine, high-dose salicylates, or antimicrobial sulfonamides/may require increased vitamin K intake.
Concomitant use with actinomycin D may reduce the efficacy of vitamin K; evidence is insufficient, and patient observation is recommended, as increased vitamin K dosage may be necessary. Concomitant use of vitamin K with coumarin or indanedione derivative anticoagulants may reduce the efficacy of these anticoagulants due to increased synthesis of procoagulant factors in the liver. When restarting oral anticoagulation therapy after taking high doses of vitamin K, it may be necessary to temporarily increase the dose of the oral anticoagulant or use an anticoagulant with a different mechanism of action, such as heparin. Vitamin K
For more complete data on interactions (18 items in total) of vitamin K1 (PHYTONADIONE), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice: 25 g/kg
Subcutaneous LD50 in mice: 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 Drugs: The rational therapeutic use of vitamin K is based on its ability to correct bleeding tendencies or bleeding. Vitamin K deficiency and its associated deficiencies in prothrombin and related clotting factors may be due to inadequate vitamin intake, absorption, or utilization, or due to the action of vitamin K antagonists. Vitamin K: Obstructive jaundice or bleeding associated with bile fistula responds rapidly to administration of vitamin K. Oral vitamin K1 (menaquinone) in combination with bile salts is safe and effective and should be used in the preoperative and postoperative care of patients with jaundice. If oral administration is not possible for any reason (for the treatment of obstructive jaundice or bile fistula), parenteral administration should be used. For more complete data on the therapeutic uses of vitamin K1 (22 in total), please visit the HSDB record page. Drug Warnings: In patients with severe liver disease as reported by the World Health Organization, high doses of menaquinone or phylloquinone may further suppress liver function.
Maternal medications generally compatible with breastfeeding: Vitamin K1: Signs or symptoms reported by infants or effects on lactation: None. (Excerpt from Table 6)
Rare hypersensitivity-like reactions have been reported following intravenous administration of phylloquinone, especially with rapid administration, occasionally resulting in death.
In neonates, especially preterm infants, due to their immature liver function, menadione sodium phosphate has been associated with hemolytic anemia, hyperbilirubinemia, and kernicterus. The risks of using phytomenadione are low unless high doses are used.
For more complete data on drug warnings for phytomenadione (21 in total), please visit the HSDB record page.

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Pharmacodynamics
Phytomenadione is a vitamin K indicated for the treatment of coagulation disorders caused by vitamin K deficiency or impaired activity leading to abnormal production of coagulation factors II, VII, IX, and X. Because vitamin K circulates in the body, it has a long duration of action and a wide therapeutic index, as high doses are tolerated. Patients should have their prothrombin time monitored during treatment, and healthcare professionals should be aware that parenteral administration increases the risk of hypersensitivity reactions.

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.)