olites. Metabolism by phase II enzymes is less well understood although glucuronidation of most metabolites, carried out by several (UDP)-glucuronosyltransferases (UGTs) with various specificities, is reported. The target of warfarin is vitamin K epoxide reductase (VKORC1), the enzyme that reduces the oxidized vitamin K and therefore regenerates the reduced form of the vitamin and essential cofactor for the carboxylation reaction of glutamate (Glu) to gamma-carboxyglutamate (Gla). The posttranslational modification of proteins known as 'vitamin K-dependent proteins' (VKDs) is an important modification that allows for the reversible, calcium-dependent, binding to negatively charged phospholipids (phosphatidylserine or phosphatidic acid) of membranes. This is particularly important for coagulation/clotting factors and natural anticoagulants, classic examples and better-characterized systems of gamma-carboxylated VKD proteins. The reaction is carried out by gamma-glutamyl carboxylase (Ggcx) and in the reaction the reduced K hydroxyquinone (KH₂) is oxidized to vitamin K 2,3-epoxide (KO). KO is converted back to KH₂ by VKORC1. The shuttling between the oxidized and reduced forms is known as the vitamin K cycle metabolic pathway. By inhibiting the cycle, warfarin precludes the modification of VKD proteins and therefore affects their function. As many of the important enzymes of the coagulation cascade are VKDs, warfarin inhibits blood clotting and is antithrombotic. However, two of the key proteins in the important anticoagulation pathway of activated protein C and the anticoagulant protein Z, are also VKDs, and inhibition of clotting can experience some delay or there may even be pro-coagulation effects, particularly at the beginning of drug treatment. Bleeding and thromboembolic effects are observed and can be rather severe. Relative dose of the drug, inter-individual variability, diet can all contribute. Warfarin can interact with drugs and foods and overall, dosing of warfarin is challenging. Foods, such as green leafy vegetables in particular but others too, are high in vitamin K. Variants in the enzymes of warfarin or vitamin K metabolism can affect the dosing of the drug and impact on its response. Polymorphisms in CYP2C9, the main enzyme of S-warfarin, and in VKORC1, the warfarin target, account for a good proportion of inter-individual variability. Side effects include necrosis, particularly of the skin, osteoporosis and vascular calcification, warfarin-related nephropathy, some likely due to VKD proteins beyond coagulation such as osteocalcin, matrix Gla protein or Gas6. More novel anticoagulant drugs are directly targeting important components of the coagulation cascade such as the activated factor X (F10a) or thrombin (F2a). There are both advantages and disadvantages in the use of these drugs, compared to the vitamin K antagonist, warfarin....(less)