Disposition of Human Urinary Kininogenase after Intravenous Administration to Dogs

The plasma inhibitors and pharmacokinetics of human urinary kininogenase (HUK) were studied in dogs after intravenous injection or after intravenous infusion over 30 min. Inhibitors of HUK in dog plasma were determined by gel filtration chromatography after incubation of 125I-HUK with dog plasma at 37°C. HUK rapidly bound with both α1-antitrypsin (α1-AT) and α2-macroglobulin (α2-M). After 5-min incubation only 36% of 125I-HUK remained free, and free 125I-HUK was not detectable after 60 min. The bound ratio was α1-AT:α2-M = 70:30. Plasma antigen concentrations of HUK were determined by sandwich enzyme immunoassay. After intravenous injection of HUK to dogs (6.25. 10−3p-nitro aniline unit (PNAU) kg−1), the concentration of HUK in plasma decreased bi-exponentially. The half-lives of the rapid phase (α-phase) and the slower phase (β-phase) were found to be 3 and 40 min, respectively. After intravenous infusion (1.67. 10−3, 5. 10−3 and 15. 10−3 PNAU kg−1 over 30 min), the kinetic parameters (MRTinf = 42–51 min, CLp = 11–12 mL min−1 kg−1, Vdss = 260–390 mL kg−1) were nearly constant over the range of the administered doses. From these results, it was clear that HUK administered intravenously bound rapidly to α1-AT and α2-M, and the complexes thus formed disappeared bi-exponentially from the plasma with a linear kinetic behaviour.