Comparative Pharmacokinetics of Coumarin Anticoagulants XXXII: Interindividual Differences in Binding of Warfarin and Dicumarol in Rat Liver and Implications for Physiological Pharmacokinetic Modeling

Abstract

This investigation was designed to determine the in vivo binding of racemic warfarin and dicumarol in the liver of individual adult male rats. The animals received single injections of one or the other drug. They were sacrificed after a period of time equivalent to several times the biological half-life of the drug, at plasma concentrations of 0.40 ± 0.10 (warfarin) or 7.7±1.1 (dicumarol) μg/ml. Drug concentrations in the liver, serum, and serum water (i.e., unbound drug in serum) were determined, and the concentration of unbound drug in the liver was calculated on the basis of the assumption that the concentrations of unbound drug in the serum and in liver water are equal. The free fraction of warfarin in the liver of 13 rats ranged from 0.06×10−2 to 0.6×10−2 and was substantially smaller than the warfarin free fraction in the serum. The free fraction of dicumarol in the liver of 10 rats ranged from 3.5×10−4 to 14×10−4 and was larger than the dicumarol free fraction in the serum. However, there was a statistically significant positive correlation between the serum and liver free fraction values of both drugs. Physiologically based pharmacokinetic modeling of protein-bound drugs, which requires estimation of protein-binding parameters in serum and tissues, must take account of the possibility of pronounced intersubject differences in the binding of such drugs in serum as well as tissues. With warfarin and dicumarol, tissue to plasma distribution ratios for liver and kidneys are much less variable (and, therefore, more suitable for pharmacokinetic modeling) than are the ratios of unbound to total concentration.