Prothrombin metabolism

Parenteral Anticoagulant-induced prothrombin deficiency hypoprothrombinemia secondary to conditions limiting absorption or synthesis of vitamin K (eg, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis) drug-induced hypoprothrombinemias due to interference with vitamin K metabolism (eg, antibiotics, salicylates) prophylaxis and therapy of hemorrhagic disease of the newborn. 

Pharmacokinetics Phytonadione is only absorbed from the Gl tract via intestinal lymphatics in the presence of bile salts. Although initially concentrated in the liver, vitamin K is rapidly metabolized, and very little tissue accumulation occurs. Parenteral phytonadione is generally detectable within 1 to 2 hours. Phytonadione usually controls hemorrhage within 3 to 6 hours. A normal prothrombin level may be obtained in 12 to 14 hours. Oral phytonadione exerts its effect in 6 to 10 hours. 

Using human physiology and in vitro data and clinically relevant input parameters (i.e., metabolic stability in human hepatocytes and microsomes as well as prothrombin time measured in various batches of human plasma) the model was extended to human. This human PK/PD model was then used to investigate the impact of the various physicochemical, pharmacokinetic and pharmacodynamic properties on the anticoagulant profile (i.e., prothrombin time) expected in man. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Ki and a 30- to 65-carbon polyprenyl side chain in vitamin K2. 

Waldron-Edward D, Chan P, Skoryna SC. 1971. Increased prothrombin time and metabolic changes with high serum aluminum levels following long-term exposure to Bayer-process alumina. Can Med AssocJ105 1297-1299. 

Drug Interactions Prolonged prothrombin times in patients receiving warfarin have been reported. Plasma half-life of pheny-toin (see p. 147) may be increased due to an inhibition of its metabolism. Methotrexate (see p. 378) levels may rise due to displacement from albumin binding sites by the sulfamethoxazole. 

Tricyclic antidepressants can interfere with the metabolism of oral anticoagulants, increase their serum concentrations, and prolong their half-lives by as much as 300% (SEDA-21,10) (161). Prothrombin activity should be carefully monitored in patients taking oral anticoagulants. 

Griseofulvin is a potent inducer of cytochrome P450 and has a significant effect on P450 expression in hepatocytes (SEDA-12, 236). It therefore increases the rate of metabolism of coumarin anticoagulants (50). However, both increases and decreases in prothrombin time have been reported (SED-12, 676) (18). 

In a prospective study of the effect of flu immunization on the prothrombin time in eight patients taking long-term anticoagulant treatment the prothrombin time was prolonged by 40%. In healthy subjects there was no significant effect on warfarin metabolism (SEDA-10, 289). 

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