Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (f_s)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between f_sand the first-order elimination rate constant (k), f_sand total clearance (CL_total),and f_sand the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f_I)showed twofold variations and were not related to f_s.The half-effective plasma concentrations (C_p50%)of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing f_s.The C_p50%values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to f_s.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of f_s (twofold), k (1.3-fold), V_d(1.5-fold), and CL_total(twofold). The intrinsic clearance (CL_intr)remained unaffected. There was no significant increase of f_Lbut a twofold increase of the L/P ratio. AE/dose and the C_p50%values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.This work was supported by the Deutsche Forschungsgemeinschaft: it is part of the Ph.D. thesis for D. T.