LOW-DOSE INFUSION OF RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR INHEALTHY-VOLUNTEERS TO INVESTIGATE THE BIODISTRIBUTION OF T-PA IN THE EARLY PHASE OF INFUSION

Earlier observations suggested deviations from expected pharmacokineti cs of recombinant tissue-type plasminogen activator (rt-PA) in the ear ly phase of a low-dose infusion. A study with two low-dose intravenous infusions of rt-PA was performed on 10 healthy volunteers in an open randomized two-way crossover design, Doses of 150 and 300 mu g rt-PA w ere administered over 40 min and blood samples were collected to measu re tissue-type plasminogen activator (t-PA) antigen concentrations. Pr e- and post-infusion data were used to predict a concentration profile during infusion without t-PA binding and these values were compared t o actual measurements with the t-PA binding. The difference between th e observed and predicted area under the concentration curve over the d uration of infusion was 49 ng min/ml (95% confidence interval (C): +21 , +78) for the 150 mu g infusion and 29 ng,min/ml (CI: -4, +61) for th e 300 mu g infusion. The average amount of rt-PA that was apparently m issing was 28 mu g (CI: +12, +44) after the 150 mu g infusion and 21 m u g (CI: -9, +52) after the 300 mu g infusion. These results indicate a distribution of t-PA over one or more compartments which might inclu de or be the endothelium. Low-dose infusions could be valuable in defi ning this distribution in various patient groups and might be relevant in relation to the measurement of endothelial dysfunction.