Warfarin forms

The 4-hydroxycomnarins undergo biotransformation similar to warfarin, forming hydroxylated metabolites at the 6 and 7 positions. These hydroxylated metabolites accoimt for 63 to 99% of the metabolic clearance of 4-hydroxycoumarins, including acenocoumarol. The metabolic clearances of R- and S-acenocoumarol are 6 and 66 times higher than those of R- and S-warfarin, respectively [68]. The metabolism of acenocoumarol is also stereoselective in favor of the S enantiomer. Sulphaphenazole competitively inhibits the 7-hydroxylation of R- and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol. Omeprazole acts as a partial inhibitor of 6- and 7-hydroxylation of acenocoumarol enantiomers [68]. 

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

Cools and Janssen [545] studied the effect of background salt on the permeability of warfarin through octanol-impregnated membranes (Millipore ultrafiltration filters, VSWP, 0.025-pm pores). At a pH where warfarin was in its ionized form, it was found that increasing background salt increased permeability (Fig. 7.7). This... 

A theoretical study (144) and several experimental studies using selectively deuterated mono-substituted benzenes (145), chlorobenzene (146), and warfarin (147) (Fig. 4.79) provided strong evidence for the stepwise mechanism. Most recently, a theoretical study using density functional calculations reported the same basic conclusion (148). The reaction proceeds by a stepwise mechanism involving initial attack of FeO3"1" on the jt system to form a tetrahedral intermediate (pathway 2). The tetrahedral intermediate then goes... 

Fig. 3. Relationship between substrate lipophilicity (log P) and ability of screened microorganisms to metabolize model substrates (AP = Aminopyrine DZ = Diazepam TE = Testosterone TH = Theophylline WF = Warfarin). Log P is the logarithm of the partition coefficient of a compound between n-octanol and a pH 7.0 aqueous buffer. Ordinates represent the % of cultures tested able to transform the substrates, independently of the extent of metabolism and number of products formed (from [185])...

Anticoagnlants, medications that block the formation of clots, have also been used. These work by preventing clots from forming around the atherosclerotic plaques that would further block blood flow. A variety of anticoagulants including warfarin (Coumadin), pentoxifylline (Trental), and aspirin have been used. 

Figure 15.15 Different forms of vitamin K and the structure of an antagonist, warfarin.

The mechanism of action of warfarin becomes apparent from the molecular details of the blood clotting process. The clotting factors VII, IX, and X require Ca ions for maximum activity. These proteins possess a novel amino acid which binds Ca ions. It is a modified form of the amino acid glutamate, as y-carboxyglutamate (Gla) which possesses two... 

Warfarin, 3-(l-phenyl-3-oxobutyl)-4-hydroxycoumarin (51 R = Ph R = H), is a clinically useful oral anticoagulant drug, which exists in two diastereomeric cyclic hemiketal forms and as the open-chain ketone (51B - SIA SIC) (84JMO1092 90MI3). Table VIII shows that the intro-... 

R)- and (S)-warfarin are in their bound forms. This takes place within the protein human serum albumin. (Adapted from Clarke et ah, 2001)... 

Lactation Warfarin appears in breast milk in an inactive form. Infants nursed by warfarin-treated mothers had no change in PT. 

Warfarin has hccn drlcrmiiicd from plasma 3f>7). Siinlics of iis metabolic fate due to the action of hepatic mixed function oxidases have profited from the use of reversed-phase columns for the determination of metabolites (368). Related studies on warfarin resistance have utilized vitamin Kt 2,3-epoxide to examine the rate of its reduction in rats to form X ilamin h the rraxMion was follitwcil x liromalxtitrapliii allv... 

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