**4. Pharmacology**

#### **4.1 Pharmacokinetics**

Warfarin is highly lipid soluble [29–31]. Between 70 and 100% of the oral intake is rapidly absorbed by the intestines with a maximum plasma concentration within 2 h after oral intake [30]. The half-life of the drug is generally more than 20 h, with a large individual variety [32]. Due to the overt lipid solubility, the major part of the drug is protein bound with less than 3% being biologically available [29]. Consequently, the agent has a slow onset of action and a long duration of activity [33]. In fact, the optimal effect is delayed for a few days, until all remaining activated factors II, VII, IX, and X are depleted from the liver and the circulation [33]. Warfarin accumulates in the liver where it exerts its effect and is inactivated through oxidative metabolism by cytochromes P450 to several isomers of water-soluble hydroxywarfarin with negligible anticoagulant activity [34, 35]. These metabolites are almost completely cleared by the kidneys [36]. The hepatic accumulation and relative easy absorption in the intestines result in an enterohepatic circulation of the drug [37]. Enterohepatic circulation is a process in which substances are secreted by the liver with bile to the intestines and subsequently absorbed again by the latter [28]. This results in recycling of the product with very little elimination.

#### **4.2 Mechanism of action**

Warfarin inhibits the enzyme vitamin K epoxide reductase that recycles oxidized vitamin K [38]. Vitamin K activates the coagulating factors prothrombin

#### *Phytochemicals in Human Health*

(factor II) and the structurally related serine proteases known as factors VII, IX, and X in the liver cells [27]. Decreasing the biological availability of vitamin K inhibits the synthesis of these essential factors and eventually leads to inhibition of the coagulation process. This means that this compound affects both the intrinsic as well as the extrinsic cascade of coagulation since prothrombin plays a central role in both of these pathways [28] and renders it a highly effective anticoagulant drug.
