Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid

The major site of action for nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases is probably within the synovial compartment. There has been little work on the disposition of NSAIDs in the synovium and most studies have involved the measurement of their concentrations in synovial fluid. The concentrations of NSAIDs are more sustained in synovial fluid than in plasma, the difference being particularly noted with NSAIDs with short elimination half-lives. The more sustained concentrations may contribute to the prolonged effect of the short half-life NSAIDs, which are usually administered at intervals longer than their half-lives in plasma. The most widely used method of kinetic analysis of NSAIDs in synovial fluid is a compartmental model in which synovial fluid is a peripheral compartment of distribution of the drug. Repeated samples of synovial fluid from individual patients are difficult to collect, but even 1 sample of synovial fluid and plasma from each patient can provide useful data when analysed using the population approach to pharmacokinetic analysis. According to the compartmental model, the mean half-lives of efflux of the NSAIDs from synovial fluid range from 1.5 to 7 hours. The mean partition coefficient of most NSAIDs between synovial fluid and plasma is approximately 0.6. The NSAIDs are highly protein-bound, and the lower mean concentrations in synovial fluid are largely because of the lower concentrations of the binding protein, albumin. The NSAIDs diffuse into and out of synovial fluid in their unbound forms, but 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 synovial fluid of the knee, but there is considerable variation between the pharmacokinetics of transfer at the 2 sites in individual patients. NSAIDs decrease 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.