Metabolic Fate of Human Urinary Kallidinogenase (SK-827) (5): Metabolism in Rats
1994 Volume 9 Issue 1 Pages 71-82
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1994 Volume 9 Issue 1 Pages 71-82
The metabolism of SK-827 was s tudied by gel filtration of plasma, urine, bile and liver homogenate after intravenous injection of 125I-SK-827 in rats.
1. Gel filtration (Sephacryl S-300 superfine) chromatograms of radioactivity in plasma, obtained after intravenous injection of 125I-SK-827, demonstrated that the radioactivity in plasma was mainly in the form of 125I-SK-827 bound to an inhibitor and free 125I-SK-827. The elimination half-lives of 125I-SK-827-inhibitor complex and free 125I-SK-827 in the plasma were calculated to be 5.8 min and 39 min, respectively.
2. Gel filtration chromatograms of radioactivity in the liver demonstrated that the radioactivity in the liver was mainly in the form of 125I-SK-827 bound to an inhibitor and free 125I-SK-827. The half-lives of 125I-SK-827-inhibitor complex and free 125I-SK-827 in the liver were calculated to be 6.6 min and 10.2 min, respectively.
3. Appearance of trichloroacetic acid soluble (TCA-soluble) radioactivity during incubation at 37°C for 2 hr of the liver slices obtained at 5, 15 and 30 min after intravenous injection of 125I-SK-827 were 9%, 39% and 51% of the radioactivity present in liver slice before incubation, respectively. This result suggests that the degradation of injected 125I-SK-827 occurred in the liver. It was found that TCA-soluble degradation product in liver slices was mainly (90%) inorganic iodine.
4. Gel filtration chromatogram of radioactivity in urine within 1 hr after injection demonstrated that the radioactivity excreted to the urine was in the form of free 125I-SK-827 (16.8% of total radioactivity) and degraded product. No radioactivity related to the 125I-SK-827-inhibitor complex was observed.
5. Gel filtration chromatogram of radioactivity in bile at 1 hr after injection demonstrated that the radioactivity in bile was in the form of 125I-SK-827 bound to inhibitors (51.2%), free 125I-SK-827 (34.3%) and degraded product (14.6%).
6. From these results, it became clear that 125I-SK-827 administered intravenously was bound by an inhibitor, and complex was cleared from the plasma by the liver. The complex taken up by the liver was rapidly degraded into low molecular weight compounds. TCA-insoluble radioactivity detected in the liver at 24 hr after administration were considerded to be endogenous high molecular weight compounds into which TCA-soluble radioactivity produced by degradation of 125I-SK-827 was incorporated.
