COMPARATIVE PHARMACOKINETICS OF COUMARIN ANTICOAGULANTS .3. FACTORS AFFECTING DISTRIBUTION AND ELIMINATION OF BISHYDROXYCOUMARIN (BHC) IN ISOLATED LIVER PERFUSION STUDIES

The kinetics of elimination of BHC in man is unusual in that the apparent first‐order rate constant for elimination appears to decrease with increasing dose. No such dose dependency is apparent in rats and certain other species of animals. The purpose of this study was to determine if this difference in BHC elimination kinetics is due to a difference in the interaction of BHC with plasma proteins of rats and man. Isolated rat livers were perfused with a mixture of red blood cells from rats and plasma from donor rats or man (two concentrations) which contained various concentrations of BHC. The concentration of BHC was determined periodically in the perfusate and terminally in the liver. It was found that the apparent rate constant for the metabolism of BHC in isolated perfused rat livers is affected by the initial concentration of drug and by the source and concentration of plasma proteins, and that it is a function mainly of the distribution of BHC between liver and plasma. There is a significant difference in the affinity of BHC to plasma proteins from man and rat, respectively, and there appears to be also a difference in the relative importance of the factors which affect BHC elimination in man and rats. Copyright © 1968 Wiley‐Liss, Inc., A Wiley Company