单次静脉注射0.355mg/kg，老年大鼠的抗凝作用高于年轻大鼠。血浆和肝脏中苯丙香豆素的消除率、分布容积、游离分数和游离浓度值在老年和年轻大鼠中没有差异。静脉注射64.3 μg/kg和不同剂量苯丙香豆素（0.02～3 mg/kg）后，肝脏中[3H]维生素K1浓度下降，[3H]维生素K1-2、3-环氧化物增加浓度取决于苯丙香豆素剂量和肝脏浓度。这些变化在老年大鼠中比在年轻大鼠中更明显[2]。

Absorption, Distribution and Excretion
Bioavailability is close to 100%
Coumarin anticoagulants pass placental barrier. /coumarin anticoagulants/
The disposition of phenprocoumon differed between male and female rats, with a substantially lower apparent volume of distribution and clearance in female rats. Although female rats had a lower sensitivity to the drug, the differences in kinetics caused an apparent equal response to the same doses and a longer duration of effect.
Samples of urine and feces were collected daily from a normal human volunteer who had received a dose of pseudoracemic phenprocoumon ...containing a tracer dose of 10 microCi of (14C)phenprocoumon... . After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). ...The urinary excretion pattern was also confirmed in four additional healthy male subjects who received a single oral dose of pseudoracemic phenprocoumon... . All the drug-related materials (both hydroxylated metabolites and parent compound) that were excreted into the urine were extensively conjugated.
...A study was conducted in 24 healthy volunteers, ages 23-28 yr, who received an oral and an IV dose of phenprocoumon 9 mg at 3 wk intervals. The following mean data were obtained after IV injection: half-life alpha 0.432 hr, half-life beta 128 hr, initial blood level 0.651 ug/ml, volume of distribution 14.41, area under the concn curve (AUC) 121 ugxhr/ml. After oral intake the following mean values were measured: Tmax 2.25 hr, Cmax 1.01 ug/ml, absorption half-life 0.553 hr, initial blood level 0.865 ug/ml, half-life beta 132 hr, AUC 164 ugxhr/ml. A total mean clearance of 20.0 (IV) and 15.1 (oral) ml/hr was calculated within the first 8 hr post dose, while values measured did not differ between 8 and 48 hr post dose. ...

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Metabolism / Metabolites
Phenprocoumon is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites. Cytochrome P450 2C9 is the principal form of human liver P-450 responsible for metabolism.
Pooled plasma from patients receiving phenprocoumon anticoagulant therapy was extracted and the following substances were characterized: phenprocoumon, and its 7-hydroxy,4'-hydroxy and 6-hydroxy derivatives; they were identified by HPLC and after methylation by quartz capillary GC-MS using the electron impact and selective ion monitoring modes. This is the first occasion when phenprocoumon metabolites have been identified in plasma; they were unconjugated and in much lower concentrations (43.2 and 2 ng/ml for the 7,4' and 6-hydroxy derivatives, respectively) than the original compound (2000 ng/ml).
...The metabolites of /pseudoracemic phenprocoumon/ were identified as the 4'-, 6-, and 7-hydroxy analogues of phenprocoumon. Virtually all of the recovered radioactivity could be accounted for by the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of both 4'-(8.1% of administered dose) and 7- (33.4% of administered dose) hydroxyphenprocoumon was highly stereoselective, giving S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of administered dose) hydroxyphenprocoumon showed little stereoselectivity (S/R ratio equal to 0.85).
Phenprocoumon is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites. Cytochrome P450 2C9 is the principal form of human liver P-450 responsible for metabolism.
Half Life: 5-6 days

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Biological Half-Life
5-6 days
Phenprocoumon (Marcumar) has a longer plasma half-life /of/ 5 days than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7-14 days).
Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12-0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6-7 days after drug administration. The binding of [3H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64 +/- 0.16 ml/h/kg mean +/- SEM) than in the healthy volunteers (0.90 +/- 0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144 +/- 14 ml/h/kg) compared with normal (113 +/- 11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5 +/- 2.9 ml/h/kg) compared with normal (35.6 +/- 3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.
...The following mean data were obtained after IV injection /of phenprocoumon/: half-life alpha 0.432 hr, half-life beta 128 hr... . After oral intake the following mean values were measured: ...absorption half-life 0.553 hr, ...half-life beta 132 hr... .

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Phenprocoumon is not approved for sale by the U.S. Food and Drug Administration (FDA). Limited information indicates that anticoagulant maternal doses of phenprocoumon produce low levels in milk. Until more data are available, shorter-acting anticoagulants are preferred, especially if the infant is younger than 2 months.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
99%

[1]. The prevalence of potential drug-drug interactions in patients with heart failure at hospital discharge. Drug Saf. 2006;29(1):79-90.

[2]. Age-dependent differences in the effect of phenprocoumon on the vitamin K1-epoxide cycle in rats. Trenk D. J Pharm Pharmacol. 1980 Dec;32(12):828-32.

Phenprocoumon can cause developmental toxicity according to state or federal government labeling requirements.
Phenprocoumon is a hydroxycoumarin that is 4-hydroxycoumarin which is substituted at position 3 by a 1-phenylpropyl group. It has a role as an anticoagulant and an EC 1.6.5.2 [NAD(P)H dehydrogenase (quinone)] inhibitor.
Coumarin derivative that acts as a long-acting oral anticoagulant.
Phenprocoumon is a Vitamin K Antagonist. The mechanism of action of phenprocoumon is as a Vitamin K Inhibitor.
Phenprocoumon is an orally available, long-acting derivative of coumarin with anticoagulant activity. Upon administration, phenprocoumon inhibits the vitamin K epoxide reductase enzyme; inhibition of this enzyme prevents the formation of the reduced, active form of vitamin K (vitamin KH2), which is essential for the carboxylation of glutamate residues of vitamin K-dependent proteins. This prevents the activation of vitamin K-dependent coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S, which abrogates both thrombin production and thrombus formation.
Phenprocoumon is only found in individuals that have used or taken this drug. It is a coumarin derivative that acts as a long acting oral anticoagulant. [PubChem] Phenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
Coumarin derivative that acts as a long acting oral anticoagulant.

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Drug Indication
Used for the prevention and treatment of thromboembolic disease including venous thrombosis, thromboembolism, and pulmonary embolism as well as for the prevention of ischemic stroke in patients with atrial fibrillation (AF).

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Mechanism of Action
Phenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
The oral anticoagulants block the regeneration of reduced vitamin K and thereby induce a state of functional vitamin K deficiency. The mechanism of the inhibition of reductase(s) by the coumarin drugs is not known. There exist reductases that are less sensitive to these drugs but that act only at relatively high concentrations of oxidized vitamin K; this property may explain the observation that administration of sufficient vitamin K can counteract even large doses of oral anticoagulants. /Oral Anticoagulants/
The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1-2,3-epoxide were studied in two healthy subjects without and with 12 hr pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concn-time profile was adequately fitted by a biexponential equation, with an avg terminal half-life of 2.0 and 1.15 hr for the administered vitamin K and its 2,3-epoxide respectively. While vitamin K1 was measurable in plasma following admin of vitamin K1-2,3-epoxide, the epoxide was not detectable following admin of vitamin K1. Following pretreatment with phenprocoumon and after iv admin of vitamin K1, both the avg half-life and area under the plasma concn-time profile of vitamin K1 were marginally reduced to 1.5 hr and 1.76 mg/l/hr respectively, while the plasma concn of vitamin K1-2,3-epoxide was readily measurable and its half-life markedly prolonged to 14.7 hr. Following pretreatment with phenprocoumon and after oral administration of vitamin K1-2,3-epoxide, no vitamin K1 was detectable in plasma and the half-life of the epoxide was 13.8 hr. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1-2,3-epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs... .
Both 4-hydroxycoumarin derivatives and indandiones (also known as oral anticoagulants) are antagonists of vitamin K. Their use as rodenticides is based on the inhibition of the vitamin K-dependent step in the synthesis of a number of blood coagulation factors. The vitamin K-dependent proteins ...in the coagulation cascade... are the procoagulant factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart-Prower factor), and the coagulation-inhibiting proteins C and S. All these proteins are synthesized in the liver. Before they are released into the circulation the various precursor proteins undergo substantial (intracellular) post-translational modification. Vitamin K functions as a co-enzyme in one of these modifications, namely the carboxylation at well-defined positions of 10-12 glutamate residues into gamma-carboxyglutamate (Gla). The presence of these Gla residues is essential for the procoagulant activity of the various coagulations factors. Vitamin K hydroquinone (KH2) is the active co-enzyme, and its oxidation to vitamin K 2,3-epoxide (KO) provides the energy required for the carboxylation reaction. The epoxide is than recycled in two reduction steps mediated by the enzyme KO reductase... . The latter enzyme is the target enzyme for coumarin anticoagulants. Their blocking of the KO reductase leads to a rapid exhaustion of the supply of KH2, and thus to an effective prevention of the formation of Gla residues. This leads to an accumulation of non-carboxylated coagulation factor precursors in the liver. In some cases these precursors are processed further without being carboxylated, and (depending on the species) may appear in the circulation. At that stage the under-carboxylated proteins are designated as descarboxy coagulation factors. Normal coagulation factors circulate in the form of zymogens, which can only participate in the coagulation cascade after being activated by limited proteolytic degradation. Descarboxy coagulation factors have no procoagulant activity (i.e. they cannot be activated) and neither they can be converted into the active zymogens by vitamin K action. Whereas in anticoagulated humans high levels of circulating descarboxy coagulation factors are detectable, these levels are negligible in warfarin-treated rats and mice. /Anticoagulant rodenticides/

C18H16O3

280.31784

280.109

435-97-2

152-72-7 (Acenocoumarol); 82-66-6 (Diphenadione); 15301-97-0 ( 15301-97-0); 81-81-2 (Warfarin; WARF42; Athrombine-K); 5543-57-7 [(S)-Warfarin]; 81-81-2 (Warfarin); 129-06-6 (Warfarin sodium); 81-82-3 (Coumachlor); 5836-29-3 ( Coumatetralyl; Endox; Racumin; Endrocide); 518-20-7 (Actosin, Anticoagulans 63, BL 5, Compound 63 link, Cumopyran, Cumopyrin, Cyclocoumarol, Cyclocumarol, Methanopyranorin, Pyranocoumarin, Pyranocumarin); 66-76-2 (Dicumarol)

54680692

FINE WHITE CRYSTALLINE POWDER
Crystals or prisms from dilute methanol

1.3±0.1 g/cm3

463.2±45.0 °C at 760 mmHg

179.5ºC

195.7±21.5 °C

0.0±1.2 mmHg at 25°C

1.638

4.77

50.44

1

3

3

21

420

0

O=C1C(C(C2=CC=CC=C2)CC)=C(O)C3=CC=CC=C3O1

DQDAYGNAKTZFIW-UHFFFAOYSA-N

InChI=1S/C18H16O3/c1-2-13(12-8-4-3-5-9-12)16-17(19)14-10-6-7-11-15(14)21-18(16)20/h3-11,13,19H,2H2,1H3

4-hydroxy-3-(1-phenylpropyl)chromen-2-one

Marcoumar, Marcumar and Falithrom; Phenprocoumon; Phenprocoumarol; Marcumar; Phenprocoumarole; Falithrom

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)

DMSO : ≥ 125 mg/mL (~445.92 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (7.42 mM) (饱和度未知) in 10% DMSO + 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 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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: ≥ 2.08 mg/mL (7.42 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL澄清DMSO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: ≥ 2.08 mg/mL (7.42 mM) (饱和度未知) in 10% DMSO + 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 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。