Studies on the Metabolic Fate of Sodium Hyaluronate (SL-1010) after Intra-articular Administration. II. Distribution, Metabolism and Excretion after Repeated Intra-articular Injection into Rabbit Knee.

Abstract

A 1 % 14C-SL-1010 solution (3mg/kg) was administered repeatedly into the cavitas articulare of left rabbit knee at 4 day intervals for a total of 7 times. 1. Residual radioactivity in synovial fluid was approximately 60% of each dose at 24hrs after the 4th and 7th administrations and was comparable to that observed after the first administration. The clearance of radioactivity from synovial fluid observed after the 7th administration was comparable to a simulated curve projected from results for the first administration study group, and no accumulation was observed as a result of repeated administration. 2. Plasma levels of radioactivity reached the steady state following the 3rd administration and gradually decreased from 5 days after the 7th administration with an elimination half-life of 106. Ohrs. The observed plasma profile of radioactivity was similar to that simulated from results of the single dose study. 3. The primary route of excretion was the expired air. The cumulative excretion of radioactivity in expired air reached the steady state after the 6th administration and reached 81.5% of the total dose at 14 days after the 7th administration. The cumulative excretion of radioactivity in urine and feces were 3.3% and 2.9%, respectively. These results were similar to those observed in the single dose study. 4. The levels of radio activity in various tissues surrounding the dosing side of the knee joint gradually increased with repeated administration. At 24hrs after the 4th administration, the level had risen to 0.9-2.8 times higher levels of that at 24hrs following the first administration, and the peak concentration observed after the 7th administration was 1.4-3.2 times higher than the level at 24hrs following the first administration. The level of radioactivity was highest in the synovial tissue and was followed in order of decreasing radioactivity by the infrapatellar fat pad, meniscus, patellar ligament, cartilage and patella. 5. The level of radioactivity in the principal tissues beyond the knee joint tended to increase gradually with repeated administration, reaching a peak at 24hrs following the 7th administration. The peak values for liver, lung, kidney, spleen, Harderian gland, adrenal gland and heart were 2.6-13.6 times higher than the levels at 24hrs after the first administration. At 14 days after the 7th administration, these concentrations had decreased to 10-60% of peak values.