title: Metabolic fate of ulinastatin (2); Pharmacokinetics in rabbits following intra-articular administration.
abstract: The absorption and distribution of ulinastatin following intra-articular administration of [125I]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 fluid, which was 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, followed by the meniscus, ligament, cartilage and patella, the radioactivities of which also declined biphasically. After intra-articular administration, the plasma concentration of total radioactivity increased slowly and reached maximum at 4.3 h, and then declined slowly in a monophasic manner with a half-life of 10.8 h. The radioactivity of the high molecular weight fraction in plasma, which reached maximum at 1.7 h after administration and then declined with a half-life of 11.8 h, was consistent with the time curve for immunoreactive ulinastatin in the plasma through 24 h after the administration. Within 8 and 24 h after administration, respectively, 1.48 and 4.66% of the administered radioactivity were transferred to the lymphatic fluid. The pharmacokinetics of [125I]ulinastatin after an intra-articular administration could be explained using a multi-compartment model in which a portion of the administered ulinastatin was absorbed via the lymphatic system. This finding suggested that ulinastatin was rapidly distributed and retained for a long period of time in the joint tissues. In addition, the pharmacokinetics of ulinastatin following intra-articular administration indicated typical flip-flop kinetics.
authors.affiliation: Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ohzawa
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Ogihara
authors.forename: Y
authors.initials: Y
authors.lastname: Nakai
authors.forename: J
authors.initials: J
authors.lastname: Ishiguro
mesh_terms: D000818:Animals; D019540:Area Under Curve; D006023:Glycoproteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007270:Injections, Intra-Articular; D007457:Iodine Radioisotopes; D008196:Lymph / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D011817:Rabbits; D014018:Tissue Distribution; D014361:Trypsin Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D006023:Glycoproteins; D007457:Iodine Radioisotopes; D014361:Trypsin Inhibitors; C028665:urinastatin