Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid

The major site of action fur nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases is probably within the synovial comp artment. There has been little work on the disposition of NSAIDs in the syn ovium and most studies have involved the measurement of their concentration s in synovial fluid. The concentrations of NSAIDs are more sustained in syn ovial fluid than in plasma, the difference being particularly noted with NS AIDs with short elimination half-lives, The more sustained concentrations m ay contribute to the prolonged effect of the short half-life NSAIDs, which are usually administered at intervals longer than their half-lives in plasm a, The most widely used method of kinetic analysis of NSAIDs in synovial fluid is a compartmental model in which synovial fluid is a peripheral compartme nt of distribution of the drug, Repeated samples of synovial fluid from ind ividual patients are difficult to collect, but even 1 sample of synovial fl uid and plasma from each patient can provide useful data when analysed usin g the population approach to pharmacokinetic analysis. According to the com partmental model, the mean half-lives of efflux of the NSAIDs: from synovia l fluid range from 1.5 to 7 hours. The mean partition coefficient of most N SAIDs between synovial fluid and plasma is approximately 0.6. The NSAIDs ar e highly protein-bound, and the lower mean concentrations in synovial fluid are largely because of the lower concentrations of the binding protein, al bumin. The NSAIDs diffuse into and out of synovial fluid in their unbound forms, b ut there is some diffusion in the protein-bound forms, particularly out of synovial fluid. The mean rates of diffusion of NSAIDs into and out of skin blisters in humans are similar to the rates of influx and efflux in the syn ovial fluid of the knee, but there is considerable variation between the ph armacokinetics of transfer at the 2 sites in individual patients. NSAIDs de crease the synthesis of prostaglandins in synovial fluid, but there are few data on the relationship between the kinetics of NSAIDs in synovial fluid and the effects on prostaglandin synthesis.