Vitamin K1 (Phylloquinone; Phytomenadione)   中文名称: 维生素K1

维生素 K1 或叶绿醌是一种异戊二烯化萘醌，仅由植物、绿藻和某些蓝细菌产生。在光系统 I 中，它作为电子转运体发挥着至关重要的作用，并且还充当电子受体以促进蛋白质二硫键的形成。叶绿醌起到维生素 K1 的作用，维生素 K1 是人类和其他脊椎动物凝血、骨骼和血管代谢所必需的维生素。绿叶蔬菜和植物油含有叶绿醌，是人类维生素K的主要膳食来源[1]。在 MAPK 通路的帮助下，维生素 K1 疗法可显着减少 Caco-2、HT-29 和 SW480 细胞系的增殖并引发细胞凋亡。同时，多胺的产量也显着下降[2]。

与减少或不改变叶绿醌摄入量的参与者相比，在随访期间增加膳食维生素 K 摄入量的参与者糖尿病发病率降低了 51%[3]。通过调节成骨细胞和破骨细胞的活性并防止高脂肪饮食产生的肥胖小鼠的骨质流失，维生素 K 治疗可以逆转高脂肪饮食对骨质恶化的影响[4]。维生素 K1 被局部涂抹在皮肤上，以减少色素沉着并治愈瘀伤。与对照组相比，外用维生素 K1 的效果在伤口收缩、上皮化周期、羟脯氨酸含量和拉伸强度等指标上显示出相当大的愈合效果[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

34.14

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.55 mM) (饱和度未知) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 EtOH 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL 生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.5 mg/mL (5.55 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清乙醇储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.55 mM) (饱和度未知) in 10% EtOH + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清乙醇储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 20 mg/mL (44.38 mM) in Cremophor EL (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。