The cellular association of sodium salicylate and indomethacin in peritoneal fluid of ascites bearing mice

Abstract

The degree of association of sodium salicylate and indomethacin with inflammatorycells was measured underin vivo conditions in ascites bearing mice. These animals had sufficient volume of inflammatory effusion in the peritoneal cavity which enabled measurement of drug concentrations extravascularly, both in the effusion and in the inflammatory cells. A single anti-inflammatory dose of 200 mg/kg sodium salicylate or 10 mg/kg indomethacin was administered orally or intraperitoneally. The peritoneal salicylate levels exceeded blood levels starting approximately 4 h following oral drug application. Indomethacin peritoneal levels were substantially lower within 6 h after oral drug intake and exceeded the blood levels at 24 h. Intraperitoneal dosing of salicylate resulted after approximately 4 h in similar vascular and extravascular drug concentrations. Indomethacin was slowly cleared from the peritoneal compartment after intraperitoneal administration. Salicylate and indomethacin accumulated under in vivo inflammatory conditions in peritoneal cells. The degree of accumulation (the intracellular concentration was at most 6 times the extracellular concentration) was dependent on compound, time of sampling, protein binding and administration route. These results were confirmed inin vitro cell association experiments. Protein appeared to affect the macro- and micropartition of these drugs. The differences in biodistribution at macro level (tissue distribution) and at micro level (cellular association) between sodium salicylate and indomethacin were sought in the apparent disparities in protein binding and affinity for protein in mouse serum and exudate.