2608 Warfarin Warfarin is an anticoagulant drug normally used to prevent blood clot formation as well as migration. Although originally marketed as a pesticide (d-Con, Rodex, among others), Warfarin has since become the most frequently prescribed oral anticoagulant in North America. Warfarin has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fetal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use. Warfarin does not actually affect blood viscosity, rather, it inhibits vitamin-k dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors. 81-81-2 54678486 C19H16O4 308.104860 Solid (MSDS, A308). 161°C 17 mg/L (at 20°C) Oral ; Inhalation ; Dermal Rapidly absorbed following oral administration with considerable interindividual variations. Also absorbed percutaneously. Warfarin 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. Metabolized stereo- and regio-selectively by hepatic microsomal enzymes. S-warfarin is predominantly metabolized by cytochrome P450 (CYP) 2C9 to yield the 6- and 7-hydroxylated metabolites. R-warfarin is metabolized by CYP1A1, 1A2, and 3A4 to yield 6-, 8-, and 10-hydroxylated metabolites. Hydroxylated metabolites may be further conjugated prior to excretion into bile and urine. UGT1A1 appears to be responsible for producing the 6-O-glucuronide of warfarin, with a possibly contribution from UGT1A10. Five UGT1As may be involved in the formation of 7-O-glucuronide warfarin. S-warfarin has higher potency than R-warfarin and genetic polymorphisms in CYP2C9 may dramatically decrease clearance of and increase toxicity of the medication. In man, the dextrowarfarin enantiomorph is metabolized by side chain reduction to a secondary alcohol, whereas levowarfarin is metabolized by oxidation of the ring, primarily to 7-hydroxywarfarin. These inactive metabolic products are to some extent conjugated with glucuronic acid, undergo an enterohepatic circulation, & are ultimately excreted in urine & stool. (A613) Route of Elimination: The elimination of warfarin is almost entirely by metabolism. Very little warfarin is excreted unchanged in urine. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. Half Life: R-warfarin t_1/2=37-89 hours; S-warfarin t_1/2=21-43 hours. LD50: 374 mg/kg (Oral, Mouse) (A308) The lowest reported lethal dose in humans is 6667 ug/kg. (A684) No indication of carcinogenicity (not listed by IARC). (L135) Warfarin is an anticoagulant drug and rodenticide derived from coumarin. As a drug it is used for the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischaemia, arterial embolism and thrombosis. (A308) Hemorrhage is the most prevalent adverse effect of oral anticoagulant therapy. The incidence of bleeding complications is related to the duration and range of therapy. (L1151) LD₅₀=374 (orally in mice) The primary antidote to warfarin poisoning is immediate administration of vitamin K1 (initially slow intravenous injections of 10-25 mg repeated all 3-6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before too much damage has been done to the victim's circulatory system. At high doses warfarin can affect the body for many months, and the antidote must be administered regularly for a long period of time. (L1257) 2009-07-05T03:18:12Z 2014-12-24T20:25:42Z Cytochrome P450 1A2 (CYP1A2) (P05177) Cytochrome P450 2C8 (CYP2C8) (P10632) Cytochrome P450 2C9 (CYP2C9) (P11712) (A308) Warfarin C01541 10033 D014859 Warfarin DB00682 3232 true Cytochrome P450 1A2 (P05177) Cytochrome P450 2C8 (P10632) Cytochrome P450 2C9 (P11712) (A308) CC(=O)CC(C1=CC=CC=C1)C1=C(O)C2=CC=CC=C2OC1=O C19H16O4 InChI=1/C19H16O4/c1-12(20)11-15(13-7-3-2-4-8-13)17-18(21)14-9-5-6-10-16(14)23-19(17)22/h2-10,15,21H,11H2,1H3 InChIKey=PJVWKTKQMONHTI-UHFFFAOYNA-N 308.3279 308.104859 Exogenous Solid 2.7 HMDB01935 CHEMBL1464 10442445 <p>Nasri W. Badran, &#8220;Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making.&#8221; U.S. Patent US4113744, issued April, 1960.</p>