Vitamin K derivatives

Although vitamin K is a fat soluble vitamin, only little stores are found in the body which have to be refilled permanently via dietary input. The role of vitamin K derived from bacteria in the colon is controversely discussed, as the concentration of biliary acids for the resorption the fatsoluble vitamin K is very low in the colon. In addition, only diseases of the small intestine lead to a deficit in vitamin K concentration which cannot be restored by K2 production of colonic bacteria. However, watersoluble vitamin Ks can be resorbed by the colonic mucosa. Maybe because of the little stores for vitamin K, the process of vitamin K-dependent carboxylation of proteins is part of a cycle with several steps during which vitamin K normally is regenerated (see Fig. 1) and thus can be used several times. 

Vitamin K promotes the hepatic y-car-boxylation of glutamate residues on the precursors of factors II, VII, IX, and X, as well as that of other proteins, e.g., protein C, protein S, or osteocalcin. Carboxyl groups are required for Ca +-mediat-ed binding to phospholipid surfaces (p, 142). There are several vitamin K derivatives of different origins Ichlorophyllous plants I<2 from gut bacteria and I<3 (menadione) synthesized chemically. All are hydrophobic and require bile acids for absorption. 

The yellow color of the AM 13,1 colonies is due to their content of compound 26. In most other cases, yellow cultures owe their color to the carotenoid zea-xanthin (Hel21) or one of the many vitamin K derivatives (e.g., menaquinone MK6 in Hel21). 

Fig. 45.5. A. Structures of vitamin K derivatives. Phylloquinone is found in green leaves, and intestinal bacteria synthesize menaquinone. Humans will convert menadione to a vitamin K active form. B. Vitamin K-dependent formation of y-carboxyglutamate residues. Thrombin, Factor VII, Factor IX, and Factor X are bound to their phospholipid activation sites on cell membranes by Ca ". The vitamin K-dependent carboxylase, which adds the extra carboxyl group, uses a reduced form of vitamin K (KH2) as the electron donor and converts vitamin K to an epxjx-ide. Vitamin K epoxide is reduced, in two steps, back to its active form by the enzymes vitamin K epoxide reductase and vitamin K reductase.

The hemolytic effect of menadione may be demonstrated also in vitro with red blood cells obtained from vitamin E-deficient rats (Rose and Gyorgy, 1960). This was first shown in vivo by Allison el al. (1956). The tetrasodium salt of the diphosphoric acid ester of 2-methyl-l, 4-naphthohydroquinone (Synkayvite ) was inactive in vitro but produced hemolysis after pretreatment with phosphatase (Rose and Gyorgy, 1960). The natural vitamin Ki was inactive in vivo as well as in vitro. Vitamin E prevents the hemolysis by vitamin K derivatives. In agreement with Nitowsky and Marks, it is... 

Even more convenient are the conditions for determining quinones[14] at platinum or carbon solid electrodes because their reversible 2-electron (or 2 one electron steps in aprotic media) reduction proceeds at considerably positive potentials. This property could be utilized in constructing an electrochemical detector for vitamin K derivatives ... 

I6I C. Warfarin baits need contain only 0 025% active principle, and rats are killed after ingesting about 5 doses the bait can be left down and the risk of acute toxicity to man or domestic animals is not serious. In common with other coumarin derivatives, warfarin reduces the clotting power of blood and death is caused by haemorrhages initiated by any slight injury. Warfarin is a vitamin K antagonist, and large oral doses of the vitamin can be given as an antidote. 

Vitamin K can antagonize coumarinic acid compounds (warfaria and its congeners) and iadandione derivatives. Vitamin K exists ia several forms including simple water-soluble meaadioae [58-27-5] (9)... 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Most oral anticoagulants are coumarin derivatives that act via vitamin K antagonism ([2] Fig. 2). Vitamin K... 

Factor IX Replacement Hemophilia B therapy may include recombinant (produced via transfection of mammalian cells with the human factor IX gene) or plasma-derived (concentrate from pooled plasma) factor IX (see Table 64-2). Guidelines for choosing the factor-concentrate formulation for hemophilia B are similar to the guidelines for hemophilia A. However, older-generation factor IX concentrates containing other vitamin K-dependent proteins (e.g., factors II, VII, and IX), called prothrombin complex concentrates (PCCs), have been associated with thrombogenic side effects. Consequently, these products are not first-line treatment for hemophilia B.11... 

Fig. 2.10 (A) Vitamin B12 derivative. (B) Structural models of VB12-4 (a) top view (b) side view (c) bottom view bottom view of hexagonal arrangement. Adapted from [60], K. Ariga et al., Colloid Surf. A, 2000, 769, 47.

In the case of ubiquinones we have already considered the ability of quinones to react with superoxide and other free radicals. Naphthoquinones, vitamin K and its derivatives, especially menadione, are the well known producers of superoxide through redox cycling with dioxygen. However, in 1985, Canfield et al. [254] have shown that vitamin K quinone reduced the oxidation of linoleic acid while vitamin K hydroquinone stimulated lipid peroxidation. Surprisingly, later on, conflicting results were reported by Vervoort et al. [255] who found that only hydroquinones of vitamin K and its analogs inhibited microsomal lipid peroxidation. 

In order to model the oxygenation of vitamin K in its hydroquinone form, a naph-thohydroquinone derivative with a 1-hydroxy group and 4-ethyl ether was prepared and its alkoxide subjected to oxidation with molecular oxygen. Products consistent with two possible mechanisms were isolated, the epoxy-quinone which must derive from a peroxy anion intermediate at the 4-position, and a 2-hydroxy product which... 

Vitamin K (phylloquinone) and similar substances with modified side chains are involved in carboxylating glutamate residues of coagulation factors in the liver (see p. 290). The form that acts as a cofactor for carboxylase is derived from the vitamin by enzymatic reduction. Vitamin K antagonists (e. g., coumarin derivatives) inhibit this reduction and consequently carboxylation as well. This fact is used to inhibit blood coagulation in prophylactic treatment against thrombosis. Vitamin K deficiency occurs only rarely, as the vitamin is formed by bacteria of the intestinal flora. 

Drugs that may interact with lepirudin and increase the risk of bleeding include thrombolytics (eg, tPA, streptokinase) and coumarin derivatives (vitamin K antagonists). 

Hypoprothrombinemia may occur in malabsorption syndromes and also the use of broad-spectrum antibiotics may produce a hypoprothrombinemia that responds readily to small doses of vitamin K. In premature infants and in infants with hemorrhagic disease of the newborn the use of vitamin K may be indicated. However, the main indication for the use of vitamin K is to antagonize the anticoagulant activity of coumarins. Oral absorption of phytonadione and the menaquinones is by the lymph while menadione and its water-soluble derivatives are absorbed directly. The absorption of phytonadione is energy-dependent and saturable. Intravenous administration of phytonadione has produced flushing, dyspnea, chest pains, and cardiovascular collapse. 

The orally effective anticoagulant drugs are fat-soluble derivatives of 4-hydroxycoumarin or indan-l,3-dione, and they resemble vitamin K. Warfarin is the oral anticoagulant of choice. The indandione anticoagulants have greater toxicity than the coumarin drugs. 

Mechanism of Action A coumarin derivative that interferes with hepatic synthesis of vitamin K-dependent clotting factors, resulting in depletion of coagulation factors II, VII, IX, and X. Therapeutic Effect Prevents further extension of formed existing clot prevents new clot formation or secondary thromboembolic complications. Pharmacokinetics ... 

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