| Popis: |
Hepatic uptake has been proposed as the major mechanism of tPA clearance from systemic circulation. However, our recent studies demonstrated that tPA was rapidly Inactivated through complexation with protease Inhibitors in dog plasma In vitro, and that tPA-inhibitor complexes were present in plasma of dogs receiving tPA. Therefore, the present work was undertaken to differentiate hepatic from extrahepatlc clearance of tPA. Pharmacokinetics of tPA were determined in anesthetized beagle dogs with either Intact hepatic circulation or with Interrupted hepatic blood flow achieved by hepatic artery ligation and portal caval shunt.Recombinant two-chain tPA was administered as an Intravenous bolus dose (80 μg/kg) and plasma active tPA concentrations were measured using a modified and validated S-2251 chromogenlc assay. Following tPA administration to Intact dogs, plasma active tPA concentration declined blexponentlally with time with 84% of the active tPA eliminated during the α-phase. The t1/2's of the a and β-phase were 1.76 ± 0.74 and 6.23 ± 1.56 min, respectively. The systemic clearance was 25.98 ± 1.13 ml/min/kg and the volume of distribution at steady state (VDss) was 73.9 ± 15.1 ml/kg. Upon the elimination of hepatic blood flow, the systemic clearance was reduced by 54% while VDss was unaffected. The contribution of plasma Inactivation of tPA to the systemic clearance was estimated from in vitro Inactivation studies In 37°C plasma. Based on the pseudo first order Inactivation rate constants of 0.184 min-1 and 0.095 min-1 at Initial tPA concentrations of 25 and 250 IU/ml respectively, clearance rates from 5.02 to 9.2 ml/min/kg were calculated. These data suggest that (1) in Intact dogs, 46% of the tPA clearance occurs extrahepatlcally and (2) Inactivation of tPA in plasma accounts for a major portion of the extrahepatlc clearance. |
