The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat.
The dithiothreitol-dependent vitamin K 2,3-epoxide (vitamin KO) reductase activity was assayed in rat liver, kidney and testis microsomes. Rat kidney and testis showed vitamin KO reductase activity. The activity was about one tenth of the activity present in liver microsomes. The effect of in vivo S-warfarin was investigated after single doses, i.e. 0.2, 0.4 and 1 mg/kg, and after its chronic administration, i.e. 4.8 micrograms/kg/hr for 3 days. At 20 hr following the acute warfarin administration vitamin KO reductase in liver microsomes was depressed in a dose-dependent way, 50, 30 and 20% of control activity. Vitamin KO reductase in testis was not affected, and in kidney reductase activity was only reduced after the highest warfarin dose, 40% of control activity. Following chronic administration of warfarin, vitamin KO reductase activity was reduced in liver as well as in kidney and testis microsomes, 15-20, 40 and 60% of control activity in liver, kidney and testis, respectively. Blood clotting activity was about 14% of normal (thrombotest). Vitamin KO reductase activity in tissue microsomes was inhibited by warfarin added in vitro. Tissue and microsomal warfarin concentration were assayed. Following the acute administration, warfarin was poorly distributed into kidney and testis. Following the chronic administration, warfarin tissue to plasma ratio was about 3 for liver, but 0.5 for kidney and testis. The results indicate that during chronic therapy with oral anticoagulants vitamin K-dependent systems in non-hepatic tissues are reduced. However, this reduction is less than the reduction of the hepatic system. This is determined mainly by the pharmacokinetic behaviour of the 4-hydroxycoumarins.
D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000201:enzymology*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology*
D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D004229:Dithiothreitol