The anticoagulant effect of a single intravenous injection of 0.355 mg/kg was higher in older rats than in younger rats. The elimination rate, volume of distribution, free fraction, and free concentration values of phenprocoumon in plasma and liver were not different in old and young rats. The concentration of [3H]vitamin K1 in the liver decreased after an intravenous injection of 64.3 μg/kg and different doses of phenprocoumon (0.02 to 3 mg/kg), and [3H]vitamin K1-2, 3 -The increase in epoxide concentration depends on the phenprocoumon dose and hepatic concentrations. These changes are more noticeable in older rats than in younger rats [2].

Absorption, Distribution and Excretion
Bioavailability is close to 100%. Coumarin anticoagulants can cross the placental barrier. /Coumarin Anticoagulants/ Phenylacecoumarin exhibits different distribution patterns in male and female rats, with female rats showing significantly lower apparent volume of distribution and clearance than male rats. Although female rats have lower sensitivity to the drug, the pharmacokinetic differences result in similar apparent responses to the same dose, with a longer duration of action. Urine and fecal samples were collected daily from a healthy volunteer who received a pseudoracemic phenylcoumarin tracer dose containing 10 microcuri (14C) phenylcoumarin. After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). …Urinary excretion patterns were also confirmed in four other healthy male subjects who received a single oral dose of pseudoracemic phenylcoumarin… Extensive binding occurred to all drug-related substances excreted in the urine, including hydroxylated metabolites and the parent compound. A study included 24 healthy volunteers aged 23 to 28 years who received oral and intravenous injections of 9 mg phenylcoumarin at 3-week intervals. The mean data obtained after intravenous injection were as follows: α-half-life 0.432 h, β-half-life 128 h, initial plasma concentration 0.651 μg/mL, volume of distribution 14.41 mL, area under the concentration-time curve (AUC) 121 μg·h/mL. The mean values obtained after oral administration were as follows: Tmax 2.25 h, Cmax 1.01 μg/mL, absorption half-life 0.553 h, initial plasma concentration 0.865 μg/mL, β-half-life 132 h, AUC 164 μg·h/mL. The total mean clearance calculated within 8 hours after administration was 20.0 mL/h (intravenous injection) and 15.1 mL/h (oral administration), respectively, while there was no significant difference between the values measured at 8 hours and 48 hours after administration. …

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Metabolism/Metabolites
Phenylacetic coumarin is primarily metabolized stereoselectively by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (the main pathway), and by reductases to reduced metabolites. Cytochrome P450 2C9 is the main P-450 enzyme responsible for metabolism in the human liver.
Mixed plasma was extracted from patients receiving phenylacetic coumarin anticoagulation therapy, and the following substances were characterized: phenylacetic coumarin and its 7-hydroxy, 4'-hydroxy, and 6-hydroxy derivatives; these substances were identified by high-performance liquid chromatography (HPLC) and analyzed after methylation using quartz capillary gas chromatography-mass spectrometry (GC-MS) combined with electron impact and selected ion monitoring modes. This is the first time that phenylcoumarin metabolites have been identified in plasma; these metabolites are unbound and at concentrations far lower than the original compound (the concentrations of the 7-hydroxy, 4'-hydroxy, and 6-hydroxy derivatives were 43.2 ng/ml and 2 ng/ml, respectively, compared to 2000 ng/ml for the original compound). The metabolites of pseudoracemic phenylcoumarin were identified as 4'-, 6-, and 7-hydroxy analogs of phenylcoumarin. Almost all of the recovered radioactive material was derived from the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of 4'- (8.1% of the administered dose) and 7- (33.4% of the administered dose) hydroxyphenylcoumarin exhibited high stereoselectivity, with S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of the administered dose) hydroxyphenylcoumarin showed lower stereoselectivity (S/R ratio of 0.85). Phenylacecoumarin is primarily metabolized stereoselectively by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (the main pathway), and can also be metabolized to reduced metabolites by reductases. Cytochrome P450 2C9 is the main P-450 enzyme responsible for metabolism in the human liver. Half-life: 5-6 days. The plasma half-life of phenylpropanoid coumarin (Marcumar) is 5 days longer than that of warfarin, with a slightly slower onset of action and a longer duration of action (7-14 days). Nine patients with biopsy-confirmed cirrhosis (dose range 0.12-0.25 mg/kg) and seven healthy volunteers (0.23 mg/kg) were orally administered phenylpropanoid coumarin. The concentrations of phenylpropanoid coumarin in plasma and urine samples were determined by high-performance liquid chromatography (HPLC) within 6-7 days after administration. The binding rate of [3H]-phenylcoumarin in the plasma of all subjects was determined by balanced dialysis. Plasma antipyrine concentrations were determined spectrophotometrically after oral administration of antipyrine (1200 mg). The total clearance of phenylcoumarin in patients with cirrhosis (1.64 ± 0.16 ml/h/kg, mean ± standard error) was higher than that in healthy volunteers (0.90 ± 0.07 ml/h/kg), but the free drug clearance in patients (144 ± 14 ml/h/kg) was not significantly different from that in healthy volunteers (113 ± 11 ml/h/kg). Conversely, the clearance of antipyrine in the cirrhosis group (17.5 ± 2.9 ml/h/kg) was significantly lower than that in healthy volunteers (35.6 ± 3.9 ml/h/kg). The clearance of phenylcoumarin via glucuronidation was less affected during cirrhosis compared to the oxidative metabolic clearance of antipyrine. The average data obtained after intravenous injection of phenylcoumarin are as follows: α-half-life 0.432 hours, β-half-life 128 hours... The average values obtained after oral administration are as follows: ...absorption half-life 0.553 hours, ...β-half-life 132 hours...

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Phenylogumatoidin has not yet received marketing authorization from the U.S. Food and Drug Administration (FDA). Limited information suggests that the concentration of phenylcoumarin in breast milk is low when the mother takes anticoagulant doses. Until more data are available, short-acting anticoagulants are recommended as a priority, especially for infants under 2 months old.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding Rate
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.

According to state or federal labeling requirements, phenylpropromin may cause developmental toxicity. Phenylopromin is a hydroxycoumarin, a 4-hydroxycoumarin with a 1-phenylpropyl group substituted at the 3-position. It has anticoagulant activity and is an EC 1.6.5.2 [NAD(P)H dehydrogenase (quinone)] inhibitor. It is a long-acting oral anticoagulant. Phenylopromin is a vitamin K antagonist. The mechanism of action of phenylpropromin is as a vitamin K inhibitor. Phenylopromin is an orally effective long-acting coumarin derivative with anticoagulant activity. After administration, phenylpropromin inhibits vitamin K epoxide reductase; inhibition of this enzyme prevents the formation of reduced active vitamin K (vitamin KH2), which is essential for the carboxylation of glutamate residues in vitamin K-dependent proteins. This prevents the activation of vitamin K-dependent coagulation factors II, VII, IX, and X, as well as anticoagulant proteins C and S, thereby inhibiting thrombin generation and thrombus formation. Phenylogumarin is found only in individuals who have used or taken this medication. It is a coumarin derivative used as a long-acting oral anticoagulant. [PubChem] Phenylogumarin inhibits vitamin K reductase, leading to the depletion of reduced vitamin K (vitamin KH2). Since vitamin K is a cofactor for the carboxylation of the N-terminal glutamate residues of vitamin K-dependent proteins, this limits the γ-carboxylation of vitamin K-dependent clotting proteins and their subsequent activation. The synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as anticoagulants C and S, is inhibited. Inhibition of three of the four vitamin K-dependent clotting factors (factors II, VII, and X) results in decreased prothrombin levels, leading to a reduction in the amount of thrombin generated and the amount of thrombin bound to fibrin. This can reduce the thrombotic tendency of thrombi.
A coumarin derivative used as a long-acting oral anticoagulant. Drug Indications For the prevention and treatment of thromboembolic diseases, including venous thrombosis, thromboembolism, and pulmonary embolism, as well as the prevention of ischemic stroke in patients with atrial fibrillation. Mechanism of Action Phenylogumarins inhibit vitamin K reductase, leading to the depletion of reduced vitamin K (vitamin KH2). Since vitamin K is a cofactor for the carboxylation of N-terminal glutamate residues in vitamin K-dependent proteins, this limits the γ-carboxylation and subsequent activation of vitamin K-dependent clotting proteins. The synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as anticoagulants C and S, is inhibited. Inhibition of three of the four vitamin K-dependent clotting factors (factors II, VII, and X) results in decreased prothrombin levels and a reduced amount of thrombin generated that binds to fibrin. This reduces the thrombogenicity of thrombi. Oral anticoagulants block the regeneration of reduced vitamin K, leading to functional vitamin K deficiency. The mechanism by which coumarin drugs inhibit reductase is not yet clear. Some reductases are less sensitive to these drugs and only function at relatively high concentrations of oxidized vitamin K; this characteristic may explain why adequate vitamin K supplementation can counteract the effects of high-dose oral anticoagulants. /Oral Anticoagulants/
This study investigated the in vivo distribution of a single intravenous injection of 10 mg vitamin K1 and vitamin K1-2,3-epoxide in two healthy subjects, who were studied without pretreatment with phenylcoumarin (0.4 mg/kg) and with a 12-hour pretreatment. For each compound administered alone, the plasma concentration-time curves were well fitted by a biexponential equation, with mean terminal half-lives of 2.0 hours and 1.15 hours for vitamin K and its 2,3-epoxide, respectively. Although vitamin K1 was still detectable in plasma after administration of vitamin K1-2,3-epoxide, the epoxide was undetectable after administration of vitamin K1. Following pretreatment with phenylcoumarin, intravenous injection of vitamin K1 slightly reduced the mean half-life and area under the plasma concentration-time curve (AUC) of vitamin K1 to 1.5 hours and 1.76 mg/L/hour, respectively. In contrast, the plasma concentration of vitamin K1-2,3-epoxide was readily measurable, and its half-life was significantly prolonged to 14.7 hours. After pretreatment with phenylcoumarin, oral administration of vitamin K1-2,3-epoxide resulted in undetectable vitamin K1 in plasma, and the half-life of this epoxide was 13.8 hours. Based on the AUC analysis, the data suggest that the effect of phenylcoumarin may not be limited to inhibiting 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 insufficient. Analysis of similar data from dogs yielded the same conclusion…
4-Hydroxycoumarin derivatives and indanedione (also known as oral anticoagulants) are both vitamin K antagonists. Their use as rodenticides works by inhibiting the vitamin K-dependent steps in the synthesis of various blood clotting factors. Vitamin K-dependent proteins in the coagulation cascade include procoagulant factors II (prothrombin), VII (prothrombin convertase), IX (Christmas factor), and X (Stuart-Proll factor), as well as coagulation inhibitory proteins C and S. All of these proteins are synthesized in the liver. Before being released into the bloodstream, these precursor proteins undergo numerous (intracellular) post-translational modifications. Vitamin K acts as a coenzyme in one of these modifications, specifically by carboxylating 10-12 glutamate residues at a specific site to generate γ-carboxyglutamate (Gla). The presence of these Gla residues is crucial for the procoagulant activity of various coagulation factors. Vitamin K hydroquinone (KH2) is the active coenzyme, which provides the energy required for the carboxylation reaction by oxidizing to vitamin K 2,3-epoxide (KO). Subsequently, this epoxide is recycled through two reduction steps catalyzed by KO reductase… KO reductase is the target of coumarin anticoagulants. Coumarin anticoagulants inhibit KO reductase, leading to rapid depletion of KH2 and effectively preventing the formation of Gla residues. This results in the accumulation of uncarboxylated clotting factor precursors in the liver. In some cases, these precursor proteins are further processed without carboxylation and (depending on the species) may appear in the bloodstream. At this point, the uncarboxylated protein is called decarboxylated clotting factor. Normal clotting factors circulate as proenzymes, participating in the coagulation cascade only after activation through limited proteolytic degradation. Decarboxylated clotting factors lack procoagulant activity (i.e., cannot be activated) and cannot be converted to active proenzymes by the action of vitamin K. While high levels of circulating decarboxylated clotting factors can be detected in humans receiving anticoagulation therapy, their levels are negligible in rats and mice treated with warfarin. /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

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)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.42 mM) (saturation unknown) in 10% DMSO + 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 20.8 mg/mL clear DMSO 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: ≥ 2.08 mg/mL (7.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO 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: ≥ 2.08 mg/mL (7.42 mM) (saturation unknown) in 10% DMSO + 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)