In Vivo Studies on the Interaction between Phenprocoumon and Acetylsalicylic Acid or Phenylbutazone
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 (CSST) of 19 ug/ml plasma and for free P (CSSF) of 3.4% of CSST 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 CSSF being 4.3% of the CSST 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 CSST 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 CSST and CSSF. Upon addition of AS the CSST and CSSF 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 CSST was found to be unaltered in plasma and IF, while the CSSF 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.