Abstract
Recombinant plasminogen activator inhibitor-1 (rPAI-1) produced and purified in active form from E. coli, was labelled with [125]-iodine using the Bolton-Hunter method. The distribution of the radiolabelled protein was determined in the rat. The greatest percentage of 1'251I-rPAI-1/(g of tissue) was found in the liver, followed by the spleen, kidney, lungs and heart. Radioactivity was detected in the urine up to 9h after injection of [251]-rPAI-1. In addition, a crossover study was performed in rabbits to determine the pharmacokinetics of unlabelled rPAI-1(100 μg/kg i.v. and 2.5 mg/kg i.v.). PAI-1 antigen levels determined by an ELISA were used to calculate pharmacokinetic parameters using a two compartment open model. Significant dose dependent changes for t 1 2 α , V d and CI p were observed while rPAI-1 cleared from the circulation in a biphasic manner with a t 1 2 β of approximately 15 min for both doses. Clearance of rPAI-1 activity closely paralleled the disappearance of the antigen. The pharmacokinetic profile of rPAI-1 with its short half-life, liver metabolism and limited tissue distribution may allow for the safe therapeutic use of rPAI-1 as an antifibrinolytic agent.
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