Metabolic fate of KRN5702: Plasma level, distribution, metabolism and excretion of 125I-KRN5702 after repeated subcutaneous administration to rats.

Abstract

The plasma levels, tissue distribution and excretion of 125I-KRN5702 after repeated subcutaneous administration were investigated in male rats. After seventh subcutaneous administration of 125I-KRN5702 at a dose of 200IU/kg, no difference in the plasma level profiles of total and trichloroacetic acid (TCA) precipitable radioactivity was observed, whereas immunoreactive radioactivity showed relatively low level when compared to that after a single administration. Both the area under the plasma concentration vs time curve (AUC) and the maximum level (Cmax) of immunoreactive radioactivity after repeated administration were 17 and 16% lower than that after single administration, respectively. We consider that the increase in utilization of this material by target organs might be responsible for increased plasma clearance. In the majority of tissues, the levels of radioactivity at 8 hours after each dose during repeated administration were same or slightly higher than those after initial administration. High levels of radioactivity were observed in the plasma, kidney and at the site of administration, independently of the numbers of injection. Whereas those in the spleen, bone marrow and thyroids were relatively higher as compared with those of the initial administration. After final administration, the most of tissues showed a maximum level of radioactivity at 8 hours after administration and then decreased in parallel with plasma level in any time interval. Beyond 48 hours after final administration, the radioactivity in the site of injection decreased to below 2 % of that at 2 hours after administration, and no accumulation in any particular organs or tissues was observed in repeated administration of 125I-KRN5702. Excretion of radioactivity in urine and feces was almost constant, i. e. 80 ?? 90% and 4 ?? 60% of each administered dose, respectively, during repeated administration. Finally, within 7th days after final administration, radioactivity excreted in urine and feces were 96.2% and 8.0% of total dosing, respectively.