Pharmacokinetics of human urinary kallidinogenase in rabbits and rats

Objective: To study the binding, degradation and concentration-time profiles of 125I-kallidinogenase in plasma after i.v. injection in rabbits. The distribution and excretion of kallidinogenase and its metabolites in urine and bile were also studied in rats. Methods: Using 125I-kallidinogenase combined with size-exclusive high performance liquid chromatography (SHPLC) or trichloroacetic acid precipitation method. Results: Determined by hydrolysis of chromogenic substrate (S-2266) of kallidinogenase, demonstrated that the enzymatic activity of 125I-kallidinogenase was similar to that of unlabelled enzyme. SHPLC analysis of plasma revealed that plasma protein bound 125I-kallidinogenase and 125I-degradation products were found after intravenous injection of various doses of the agent. Terminal half-lives of 125I-kallidinogenase-protein complex (AUC) after i.v. 5 x 10-3, 15 x 10-3, and 45 x 10-3 pNAu·kg-1 were (1.28 +- 1.31), (2.18 +- 1.08) and (2.03 +- 0.32) h, respectively. AUC increased with dose while clearance was similar. Maximal percentage of bound serum 125I-kallidinogenase in vitro was (94.3 +- 0.77)% and equilibrium dissociation constant (Kd) was 8.9 x 10-8 mol·L-1. Levels of acid precipitable radioactivity in different organs were in a descending order: urinary system, the highest blood abundant organs the next and cerebral cortex the lowest. (96.9 +- 3.3)% of injected radioactivity was excreted within 2 days and the major route was urinary system. Conclusions: 125I-kallidinogenase was rapidly bound to plasma protein with high affinity after i.v. injection. The pharmacokinetics of 125I-kallidinogenase was rapidly bound to plasma protein with high affinity after i.v. injection. The pharmacokinetics of 125I-kallidinogenase-protein complex was linear within dosage range studied in rabbits. 125I-kallidinogenase was mainly distributed in blood abundant organs, not able to across blood-brain barrier and excreted through urine after i.v. injection in rats