METABOLIC-FATE OF ULINASTATIN(2) - PHARMACOKINETICS IN RABBITS FOLLOWING INTRAARTICULAR ADMINISTRATION

The absorption and distribution of ulinastatin following intra-articul ar administration of [I-125]ulinastatin to rabbits were determined and kinetic analysis using a multi-compartment model was performed. At 4 h after administration, the content of radioactivity in the synovial f luid, which mas comparable to that of the immunoreactive ulinastatin, was 14.51% of the dose and decreased in a biphasic manner. The highest level of radioactivity was observed in the synovial membrane, followe d by the meniscus, ligament, cartilage and patella, the radioactivitie s of which also declined biphasically. After intra-articular administr ation, the plasma concentration of total radioactivity increased slowl y and reached maximum at 4.3 h, and then declined slowly in a monophas ic manner with a half-life of 10.8 h. The radioactivity of the high mo lecular weight fraction in plasma, which reached maximum at 1.7 h afte r administration and then declined with a half-life of 11.8 h, was con sistent with the time curve for immunoreactive ulinastatin in the plas ma through 24 h after the administration. Within 8 and 24 h after admi nistration, respectively, 1.48 and 4.66% of the administered radioacti vity were transferred to the lymphatic fluid. The pharmacokinetics of [I-125]ulinastatin after an intra-articular administration could be ex plained using a multi-compartment model in which a portion of the admi nistered ulinastatin was absorbed via the lymphatic system. This findi ng suggested that ulinastatin was rapidly distributed and retained for a long period of time in the joint tissues. In addition, the pharmaco kinetics of ulinastatin following intra-articular administration indic ated typical flipflop kinetics.