In Vivo Studies on the Interaction between Phenprocoumon and Acetylsalicylic Acid or Phenylbutazone

Abstract

After intravenous injection of a loading dose of ³H-phenprocoumon (P) to rabbits, the drug was infused for a period of 10 hours. By this procedure a steady state concentration for total P (C_SST) of 19 ug/ml plasma and for free P (C_SSF) of 3.4% of C_SST was attained immediately after injection. Interstitial fluid (IF) was drawn from tissue cages implanted subcutaneously according to D. CHISHOLM et al. (Brit.med.J. 1, 569–573, 1973). After 7 to 10 hrs the total concentrations of P in this fluid amounted to 55% of the corresponding plasma value, the C_SSF being 4.3% of the C_SST in the IF. 5 hours after starting the application of P acetylsalicylic acid (AS) or phenylbutazone (PB) were also administered by combination of a loading dose and subsequent infusion. The C_SST of AS and of PB were in the range of 100 ug/ml and 70 ug/ml plasma, respectively. Immediately upon addition of AS or PB the free fraction of P in the plasma increased to 4.3% and 5.5% resp., and in the IF to 6,4% (AS) and 6.1% (PB), and were permanentely maintained. In spite of the fact that both AS and PB reduce the protein binding of P in plasma and IF, opposite effects were observed with resprect to C_SST and C_SSF. Upon addition of AS the C_SST and C_SSF in both compartments were reduced to lower levels (75%). This may be explained by diffusion of displaced P into the intracellular space, where the protein binding appears not to be influenced by AS. After addition of PB, however, the C_SST was found to be unaltered in plasma and IF, while the C_SSF were considerably increased. It may be assumed that the PB will intracellularly compete with protein bound P thus increasing the concentration of free P also within the cells. Therefore a concentration gradient for free P does not exist between extra- and intracellular space. Hence, after administration of PB the free P concentrations are elevated in all compartments accessible for P and PB.