Endothelial binding of recombinant tissue plasminogen activator: quantification in vivo using a recirculatory model.
Binding of tissue plasminogen activator (t-PA) to the endothelium may be important in the prevention of thrombus formation. The aim was to develop a method to quantify endothelial binding in vivo. Nine healthy male volunteers received a 40 min continuous infusion with low dose recombinant t-PA (3.75 micrograms/min) and an indocycanine green infusion (0.5 mg/min) as control. A three-compartment recirculatory model was developed to account for non-specific circulatory delay effects. t-PA antigen, activity and t-PA/PAI-1 complex profiles showed a marked delay in increase at the beginning of the infusion. A reversible and concentration-dependent binding component was incorporated in the model which resulted in an accurate description of the t-PA concentration profile. t-PA binding was characterized by a dissociation constant of 5.9 ng/ml (SEM 1.8, CV 0%; fixed) and a binding capacity of 70 micrograms t-PA (SEM 10, CV 48%). This model can be used as a tool to quantify the ability of the endothelium to bind t-PA.
Kemme
Michiel J
MJ
Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands. mk@CHDR.nl
Schoemaker
Rik C
RC
Burggraaf
Jacobus
J
van der Linden
Monique
M
Noordzij
Marina
M
Moerland
Matthijs
M
Kluft
Cornelis
C
Cohen
Adam F
AF
D000328:Adult; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology
D010959:Tissue Plasminogen Activator