Abstract
Toxic doses of racemic [ 14C]warfarin (3-(α-acetonylbenzyl)-4-hydroxycoumarin) were administered (0.8 mg/kg, po) for 5 days to rats fed one of three different purified diets, 25% casein, 8% casein, and casein-free. Four rats from each dietary group were bled at 6, 30, 54, 78, and 102 hr after the initial dose. Rats consuming a casein-free diet maintained higher total plasma warfarin levels than rats fed a 25 or 8% casein diet. Additionally, percentage free warfarin levels of 0% casein rats were greater than those of 25 and 8% groups through the first 78 hr. An increase in percentage unbound drug was therefore most likely associated with a decrease in total plasma clearance. The protein-free rats had a more rapid increase in prothrombin time and lower plasma albumin levels than rats fed either a 25 or 8% casein diet. A significant correlation was found between the percentage free fraction of warfarin and the prothrombin response in each of the three dietary groups. A negative correlation was found between percentage free plasma warfarin and plasma albumin concentration in each of the three dietary groups. A correlation was found between total plasma warfarin and prothrombin time for the rats on the 0% protein diet. It was concluded that the quantity of dietary protein was an important factor in determining the response of rats to toxic levels of warfarin.
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