Determinants of clearance of tissue-type plasminogen activator (t-PA) from the circulation

Abstract

Elucidation of determinants of the clearance of tissue-type plasminogen activator (t-PA) from the circulation is necessary in order to identify subjects in whom dose regimens will require modification in order to maximise safety and efficiency. Preliminary observations in hepatectomised animals suggest that the liver is a primary site of metabolism of t-PA. To determine whether alterations in hepatic blood flow simulating those encountered clinically in patients with congestive heart failure affect the rate of clearance of t-PA from plasma, t-PA was administered intravenously to nine dogs before and after hepatic blood flow had been reduced by induction of systemic hypotension. Hepatic blood flow was evaluated sequentially by analysis of the plasma clearance of carbon-l4 labelled taurocholic acid, a novel tracer selected because of its high hepatic extraction fraction. The extraction fraction of t-PA by the liver was measured directly by assay of the concentration of t-PA in simultaneously obtained arterial and hepatic venous blood samples. Both the concentration of t-PA antigen and t-PA functional activity were determined. t-PA was cleared from plasma in a bi-exponential manner with an early brisk (α) and a relatively less steep brisk (β) phase. At baseline, the half-life ( t, 1 2 ) of t-PA during the α-phase was 3.5±0.2 (±SEM) min. It did not change appreciably, averaging 4.4±0.6 min, despite marked reduction of hepatic blood flow accompanying profound hypotension with a 45%) reduction of mean arterial pressure. Similarly, the half-life of t-PA during the β-phase of clearance at baseline (12.6±1.1 min) was not significantly altered by reduction of hepatic blood flow (12.5 ± 0.9 min). The hepatic extraction fraction of t-PA declined progressively with time after administration of bolus of t-PA from 41±27%-0 (n = 3) 1 min after injection to 34 ± 16%, (n = 4), 14 ± 13% (n = 6) and 10 ± 11% (n = 6) 12, 20 and 30 min after injection in normotensive animals. Overall, the extraction fraction of t-PA by the liver increased 66.2±19.2% above the baseline level when hypotension was present compared to the case with normotension. This increase in extraction fraction associated with a diminution of hepatic blood flow probably accounts for the relatively consistent rate of clearance of t-PA from the circulation despite reduction of hepatic blood flow. The results obtained indicate that the rate of clearance of t-PA from the circulation does not diminish markedly despite profound hemodynamic perturbations and reduction of hepatic blood flow to levels simulating those likely to be encountered in patients with severe cardiovascular disease. Accordingly, they suggest that major modifications in dosage will not be required to compensate for derangements in hepatic perfusion. The bi-exponential nature of clearance of t-PA from the circulation and the diminished hepatic extraction fraction as a function of time underscore the likelihood that accumulation of t-PA may be encountered with prolonged administration.