Comparative pharmacokinetics of coumarin anticoagulants XXI: effect of plasma protein binding on distribution kinetics of warfarin in rats

Abstract

The purpose of this investigation was to determine the effect of plasma protein binding on the pharmacokinetic parameters for warfarin that are used conventionally to describe its distribution kinetics on the basis of the time course of plasma warfarin concentrations. Following rapid intravenous injection, warfarin concentrations in the plasma of 14 selected adult male rate declined triexponentially, with the terminal exponential phase starting at about 5 hr. The free fraction, f, of warfarin in the serum of individual animals ranged from 0.303 X 10(-2) to 2.89 X 10(-2). The parameters of the equation Ct = Pe-theta + Ae-alphat + Be-betat for plasma concentration Ct at time t were obtained from the experimental data by nonlinear least-squares computer fitting and varied markedly between animals. Strong and highly statistically significant positive correlations with f were obtained for P, B, and beta, but no significant correlation was found for A, theta, and alpha. Rate constants and apparent volumes for a three-compartment open mammillary model with elimination from the central compartment were calculated. No apparent correlation was found between f and the intercompartment distribution rate constants. However, strong positive correlations between f and the elimination rate constant, the volume of the central compartment, and the volume of distribution, V area, were observed. There also was a strong linear correlation between f ant total clearance. Excellent replication of the experimental data was obtained when the experiment were repeated in some animals after 2 weeks. A detailed analysis of practical pharmacokinetic problems associated with and revealed by such repeated experiments is presented.