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.

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.

[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

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.
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.
Vitamin K1 has been reported in Camellia sinensis, Alhagi persarum, and other organisms with data available.
Phytonadione is an analogue of the naphthoquinone vitamin K found in plants. The vitamins K are essential for blood coagulation as it is necessary for the hepatic synthesis of the coagulation factors II, VII, IX, and X; deficiency results in a bleeding diathesis. These vitamins are lipo-soluble; absorption via intestinal lymphatics requires the presence of bile salts. (NCI04)
Vitamin K is the term "vitamin K" refers to a group of chemically similar fat-soluble compounds called naphthoquinones: vitamin K1 (phytonadione) is found in plants and is the primary source of vitamin K for humans through dietary consumption, vitamin K2 compounds (menaquinones) are made by bacteria in the human gut, and vitamin K3 (menadione) is a water-soluble preparation available for adults only. Vitamin K is necessary for the liver to produce the coagulation factors II, VII, IX, and X, as well as the clotting factors protein C, protein S, and protein Z; vitamin K deficiency can result in deficiencies of these coagulation factors and excess bleeding. An injection of vitamin K is routinely given to newborn infants to prevent vitamin K deficiency bleeding, also known as hemorrhagic disease of the newborn. Vitamin K deficiency is rare in adults but may result from chronic malnutrition or an inability to absorb dietary vitamins.
Phylloquinone is often called vitamin K1. It is a fat-soluble vitamin that is stable to air and moisture but decomposes in sunlight. It is found naturally in a wide variety of green plants. Phylloquinone is also an antidote for coumatetralyl. Vitamin K is needed for the posttranslational modification of certain proteins, mostly required for blood coagulation.
A family of phylloquinones that contains a ring of 2-methyl-1,4-naphthoquinone and an isoprenoid side chain. Members of this group of vitamin K 1 have only one double bond on the proximal isoprene unit. Rich sources of vitamin K 1 include green plants, algae, and photosynthetic bacteria. Vitamin K1 has antihemorrhagic and prothrombogenic activity.
See also: Broccoli (part of); Kale, cooked (part of); Cholecalciferol; phytonadione (component of) ... View More ...

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Drug Indication
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.

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Mechanism of Action
Vitamin K is a cofactor of gamma-carboxylase. Gamma carboxylase attaches carboxylic acid functional groups to glutamate, allowing precursors of factors II, VII, IX, and X to bind calcium ions. Binding of calcium ions converts these clotting factors to their active form, which are then secreted from hepatocytes into the blood, restoring normal clotting function. Vitamin K may also carboxylate matrix proteins in chondrocytes, inhibiting calcification of joints, and may increase type II collagen. The role of vitamin K in osteroarthritis, bone density, and vascular calcification is currently under investigation.
Vit k is necessary for formation of prothrombinogen & other blood clotting factors in liver. During clotting, circulating prothrombin is required for production of thrombin; in turn, thrombin converts fibrinogen to fibrin, network of which constitutes clot. /vit k/
In normal animals and man, phyltonadione ... /is/ virtually devoid of pharmacodynamic activity. In Animals and man deficient in vitamin k, the pharmacological action of vitamin k is identical to its normal physiological function, that is, to promote hepatic biosynthesis of prothrombin (factor ii), proconvertin (factor vii), plasma thromboplastin component (ptc, christmas factor, factor ix), and Stuart factor (factor x).
On the basis of studies of microsomal metabolism in vitro and studies in rats and mice in vivo, /it was suggested/ that vitamin K may be mutagenic by affecting the mixed-function oxidase system which metabolizes benzo(a)pyrene. Phylloquinone at a high concentration (200 umol/l) inhibited the conversion of benzo(a)pyrene to its more polar metabolites, ... . Paradoxically, at a lower concentration of phylloquinone (25 umol/l), ... the metabolism of benzo(a)pyrene was increased. In this system, therefore, .... phylloquinone could either potentiate or inhibit it, depending on the concentration. This overall weaker inhibitory effect of phylloquinone could be due to the low solubility of this lipophilic compound, but it is difficult to explain the mechanism of the enhanced metabolism of benzo(a)pyrene at lower concentrations of phylloquinone.

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。