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.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在用华法林处理的动物中，大部分叶绿素被代谢为叶绿素氧化物。
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.
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.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
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.
来源:DrugBank
吸收、分配和排泄
消除途径
静脉给药的叶绿素在5天内有36%通过粪便排出，3天内22%通过尿液排出。
Intravenous phylloquinone is 36% eliminated in the feces in 5 days and 22% recovered in urine in 3 days.
来源:DrugBank
吸收、分配和排泄
分布容积
菲洛奎酮的稳态分布容积在接受phenprocoumon治疗的患者中为20 ± 6升。
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.
来源:DrugBank
吸收、分配和排泄
关于维生素K的排泄了解得很少。高粪便中的维生素K浓度可能是由于肠道内细菌合成的。
Little is known about the excretion of vitamin K. High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
[EN] PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS D'ACIDE PHOSPHONIQUE ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DU RÉCEPTEUR P2Y12
申请人：ACTELION PHARMACEUTICALS LTD
公开号：WO2009069100A1
公开（公告）日：2009-06-04
The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. (I).
[EN] BIOACTIVE CONJUGATES FOR OLIGONUCLEOTIDE DELIVERY<br/>[FR] CONJUGUÉS BIOACTIFS POUR L'ADMINISTRATION D'OLIGONUCLÉOTIDES
申请人：UNIV MASSACHUSETTS
公开号：WO2017030973A1
公开（公告）日：2017-02-23
Provided herein are self-delivering oligonucleotides that are characterized by efficient RISC entry, minimum immune response and off-target effects, efficient cellular uptake without formulation, and efficient and specific tissue distribution.
[EN] PRODRUGS OF D-ISOGLUTAMYL-[D/L]-TRYPTOPHAN<br/>[FR] PROMÉDICAMENTS DE D-ISOGLUTAMYL-[D/L]-TRYPTOPHANE
申请人：APOTEX TECHNOLOGIES INC
公开号：WO2012129671A1
公开（公告）日：2012-10-04
Provided are carboxylic ester derivatives of formula (I), methods of preparing them, and methods for using them. These compounds are prodrugs of D-isoglutamyl-[D/L]-tryptophan. The in vitro bioconversion of some of the prodrugs to the parent drug D-isoglutamyl-D-tryptophan (or thymodepressin) was tested in human hepatocytes and in human blood. In vivo pharmacokinetic studies following oral administration of some of the prodrugs to rats are also reported.
[EN] PRODRUGS OF D-GAMMA-GLUTAMYL-D-TRYPTOPHAN AND D-GAMMA- GLUTAMYL-L-TRYPTOPHAN<br/>[FR] PROMÉDICAMENTS DE D-GAMMA-GLUTAMYL-D-TRYPTOPHANE ET D-GAMMA-GLUTAMYL-L-TRYPTOPHANE
申请人：APOTEX TECHNOLOGIES INC
公开号：WO2012129680A1
公开（公告）日：2012-10-04
The present invention provides pro-drugs of D-gamma-glutamyl-[D/L] -tryptophan, said pro-drugs are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein G is C1-C8 alkyl or benzyl, T is C1-C8 alkyl or benzyl, and * is a chiral carbon in a (R) or (S) configuration, provided that when * is in the (R) configuration, at least one of G and T is C5-C8 alkyl; and use of compounds of Formula I in a pharmaceutical composition.
