ワルファリン 化学特性,用途語,生産方法
外観
白色〜ほとんど白色, 結晶性粉末〜粉末
溶解性
水:17mg/l(20℃)。ベンゼン、エーテル、シクロヘキサンにわずかに溶ける。メタノール、エタノール、イソプロパノールに可溶。アセトン:65、クロロホルム:56、ジオキサン:100(g/l、20℃)エタノール及びアセトンに溶け、水にはほとんど溶けない。
解説
ワルファリン，化学式 C19H16O4 。4-オキシクマリンとα-ベンジルアセトンを縮合させて合成する。水，ベンゼンには不溶，アルコールには可溶，アセトン，ジオキサンには易溶 (ナトリウム塩は水に可溶) 。融点 159～161℃。殺鼠剤として使用される。ただし，少量ずつ連日摂取され，ねずみの血液中にある程度の蓄積がなされ，かつある期間持続される必要がある。 0.25～0.5%濃度に混ぜた餌を5日以上連続摂取すると効果が現れる。市販品にはデンプン，色素，砂糖などを混ぜて錠剤にしたものもある。トモリンも類似化合物を主剤とした殺鼠剤である。
用途
農薬(殺ソ剤)
効能
抗凝固薬, ビタミンK拮抗薬
説明
Warfarin was the first of the synthetic anticoagulant
rodenticides with structural features inspired
by a natural product (88). This prototype coumarin derivative
was developed in the 1940s by systematically altering
the structure of dicumarol (46), recognized earlier as the
causative agent of the sweet clover disease causing severe
bleeding in grazing cattle (89). These rodenticides act by
inhibiting the oxidoreductive recycling of vitamin K, a
cofactor necessary for prothrombin synthesis involved in
blood coagulation.
化学的特性
Warfarin is a colorless, odorless crystalline
solid.
使用
Coumadin is widely used as an anticoagulant for various systemic diseases such as venous thromboembolism, cardiac arrhythmia, following myocardial infarction, and hematologic abnormalities, among others. However, the efficacy of coumadin for CRVO is not established. It was reported that 13 of 354 patients taking warfarin developed CRVO despite maintaining therapeutic levels of the anticoagulant.
主な応用
Warfarin is an anti-coagulant used to prevent heart attacks, strokes, and the formation of blood clots. It interferes with the use of vitamin K in the required carboxylation of several vitamin K-dependent proteins in the clotting cascade, preventing the initiating of clotting. (±)-Warfarin is a racemic mixture of 2 optically active isomers. (±)-Warfarin has a half-life of 36-42 hours in circulation, bound to plasma proteins, and accumulates in the liver, where the two isomers are metabolized by different pathways.
世界保健機関（WHO）
Warfarin, a coumarin anticoagulant, was introduced into medicine
in 1950 for the prevention and managementof thrombo-embolic disorders. Its use
during the first trimester of pregnancy has been associated with birth
malformations, particularly in relation to cranial and limb development, and there
have been reports of foetal death due to haemorrhage following administration of
the drug during the late stages of pregnancy. The decision of the Egyptian agency
to requrie a warning regarding teratogenicity to be included in the approved
information of products containing warfarin beings the text of the package insert in
line with those approved in other countries. Warfarin is included in the WHO Model
List of Essential Drugs.
反応プロフィール
Warfarin is incompatible with the following: Strong oxidizers .
健康ハザード
Warfarin is classified as very toxic. Probable oral lethal dose in humans is 50-500 mg/kg, between 1 teaspoon and 1 ounce for a 150 lb. person. Material is an anticoagulant. Toxic effects other than hemorrhage are rarely seen in humans. Material is believed to be teratogenic in humans. Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure.
火災危険
Contact with strong oxidizers may cause fires and explosions. Toxic gases and vapors (e.g., carbon monoxide) may be released in heating to decomposition. Avoid strong oxidizers.
农业用途
Rodenticide: Warfarin and its sodium salt is an anticoagulant rodenticide used for controlling rats and house mice in and around
homes, animal and agricultural premises, and commercialand industrial sites. It is effective in very low dosages. About
a week is required before a marked reduction in the rodent
population is noticeable. Rodents do not become bait-shy
after once tasting warfarin; they continue to consume it until its anti-clotting properties have produced death through
internal hemorrhaging. It can be used year-after-year wherever a rodent problem exists. Warfarin and its sodium salt
are only slightly dangerous to humans and domestic animals
when used as directed, but care must be taken with young
pigs, which are especially susceptible. The sodium salt is also
used to treat people with blood hypercoagulation problems.
Registered for use in EU countries
. Registered for use in
the U.S.
応用例（製薬）
A group of naturally occurring antibiotics chemically related
to the coumarin group of anticoagulants. The best known
is novobiocin, but a few naturally occurring coumarins and
some semisynthetic derivatives have been studied. They
share a narrow range of antimicrobial activity largely directed
against aerobic Gram-positive organisms. Novobiocin inhibits
susceptible strains of Staph. aureus (including β-lactamaseproducing
and methicillin-resistant strains), Str. pyogenes and
Str. pneumonia at a concentration of 0.1–2 mg/L and it has
been considered for the treatment of infection with multiresistant
Staph. aureus and other Gram-positive cocci. However,
since resistance arises readily and side effects are common,
the general consensus is that it no longer has a place in antibacterial
therapy.
There has been some revived interest in coumarins as
potentiating agents of antineoplastic drugs.
製品名
ARAB RAT DETH®; ATROMBINE-K®;
BRUMIN®; COMPOUND 42®; D-CON®; CO-
RAX®; DETHMORE®; EAGLES-7®; EASTERN
STATES DUOCIDE®; GROVEX SEWER BAIT®;
HOPKINS BAR BAIR®; HOPKINS COV-R-TOX®;
HOPKINS RODEX®; KILLGERM SEWARIN P®;
KILMOL®; LIQUA-TOX®; MAR-FIN®; MOUSE
PAK®; PLUSBAIT®; RAT-A-WAY®; RAT-B-GON®;
RAT-O-CIDE®; RAT-GARD®; RAT & MICE BAIT®;
RATRON®; RATS-NO-MORE®; RATTUNAL®; RAX®;
RCR SQUIRREL KILLER®; RENTOKIL®; RENTOKIL
BIOTROL®; RODEX BLOX®; RODENTEX®; RO-
DETH®; RODEX®; ROUGH & READY MOUSE MIX®;
SAKARAT®; SOLFARIN®; SOREXA PLUS®; SOREX
CR1®; SEWARIN®; SPRAY-TROL BRANCH®; TWIN
LIGHT RAT AWAY®; RODEN-TROL®; WARFARAT®;
WARF COMPOUND®; VAMPIRINIP®
Sodium Salt: ATHROMBIN®; LIQUA-TOX®;
PANWARFIN®; RATSUL SOLUBLE®; TINTORANE®;
VARFINE®; WARAN®; WARCOUMIN®; WARFILONE®
作用機序
Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral,
intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at
approximately 3 hours. Its anticoagulant effect is not immediately present, however, following
initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors
with normal activity are cleared and those that have not been carboxylated because of the actions of
warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline
in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability
(25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with
other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent.
Therefore, any other substance that displaces bound drug from protein binding sites increases the
levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by
hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is
quite long, both of which presumably result from the high degree of plasma protein binding.
薬物動態学
Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral,
intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at
approximately 3 hours. Its anticoagulant effect is not immediately present, however, following
initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors
with normal activity are cleared and those that have not been carboxylated because of the actions of
warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline
in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability
(25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with
other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent.
Therefore, any other substance that displaces bound drug from protein binding sites increases the
levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by
hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is
quite long, both of which presumably result from the high degree of plasma protein binding.
安全性プロファイル
A human poison by
ingestion. Poison by inhalation and
intravenous routes. Moderately toxic by skin
contact, subcutaneous, and intraperitoneal
routes. Human systemic effects by ingestion:
hemorrhage, ulceration or bleeding from
small intestine, blood clotting factor change.
Human reproductive effects by ingestion
and intramuscular routes: fetal death and
physical abnormalities at birth. Human
teratogenic effects include developmental abnormalities of the craniofacial area,
musculoskeletal system, and respiratory
system. An experimental teratogen. Other
experimental reproductive effects. Used as
an oral anticoagulant and as a rodenticide.
When heated to decomposition it emits
acrid smoke and fumes.
職業ばく露
Warfarin is used as an oral anticoagulant
and as a rodenticide or rat poison.
発がん性
No data suggest that warfarin is either
mutagenic or carcinogenic.
環境運命予測
Photolytic. Warfarin may undergo direct photolysis since the pesticide showed an
absorption maximum of 330 nm (Gore et al., 1971)
Chemical/Physical. The hydrolysis half-lives at 68.0°C and pH values of 3.09, 7.11
and 10.18 were calculated to be 12.9, 57.4 and 23.9 days, respectively. At 25°C and pH
7, the half-life was estimated to be 16 years (Ellington et al., 1986)
代謝
Warfarin and other coumarin derivatives undergo extensive hepatic oxidative metabolism catalyzed
by CYP2C9 isozyme to give 6- and 7-hydroxywarfarins as the major inactive metabolites. Warfarin
also undergoes, to a lesser extent, reductive metabolism of the ketone on the C-3 side chain to a
pair of pharmacologically active, diastereomeric 2-hydroxywarfarins). Almost no
unchanged drug is excreted in the urine. As expected, those individuals with compromised hepatic
function are at greater risk for warfarin toxicity secondary to diminished clearance. Many of the
drug–drug interactions are associated with enhanced or inhibited metabolism of warfarin via
CYP2C9 induction or inhibition. Many additional drugs and conditions have profound effects on
warfarin therapy. A partial list of these factors is shown in Table 31.2.
輸送方法
UN3027 Coumarin derivative pesticides, solid,
toxic, Hazard Class: 6.1; Labels: 6.1-Poisonous materials.
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1;
Labels: 6.1-Poisonous materials, Technical Name Required.
純化方法
dl-Warfarin crystallises from EtOH or MeOH. UV: max at 308nm ( 13,610) in H2O. The acetate has m 117-118o, the O-triflate has m 90-91o, and the 2,4-dinitrophenylhydrazone has m 215-216o. It is an effective anticoagulant and rodenticide. [West et al. J Am Chem Soc 83 2676 1961, HPLC: Banfield & Rowland J Pharm Sci 72 921 1983, Beilstein 17 III/IV 6794.]
dl-Warfarin is resolved via recrystallisation of the quinidine salt, and the free acids are recrystallised (70g) from 600mL of 80% aqueous Me2CO. Large prismatic crystals of the pure enantiomers are obtained by slow crystallisation from Me2CO or AcOH. The solubilities of the pure enantiomers at 25o are 11.2% in Me2CO and 2.6% in AcOH, whereas the racemate has solubilities of 6.5% in Me2CO and 2% in AcOH. The IR spectra are the same with max (CHCl3) at 2.78 (w), 5.88, 6.16 and 6.38. [West et al. J Am Chem Soc 83 2676 1961, Cbz-proline diastereoisomeric esters were used for HPLC analysis: Banfield & Rowland J Pharm Sci 72 921 1983.] Poisonous, anticoagulant and rodenticide.
不和合性
Incompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explosions.
Keep away from alkaline materials, strong bases,
strong acids, oxoacids, epoxides. Dust mixtures with air
may cause explosion.
廃棄物の処理
Consult with environmental
regulatory agencies for guidance on acceptable disposal
practices. Generators of waste containing this contaminant
(≥100 kg/mo) must conform to EPA regulations governing
storage, transportation, treatment, and waste disposal.
Incineration.
ワルファリン 上流と下流の製品情報
原材料
準備製品