Recent Findings on the Pharmacokinetics of Non-Steroidal Anti-Inflammatory Drugs in Synovial Fluid

Abstract

Synovial fluid concentration is considered to be an important determinant of clinical response to non-steroidal anti-inflammatory drugs (NSAIDs). Trans-synovial transport of these drugs is a process of limited diffusion, governed partly by the pharmacological characteristics of NSAIDs and partly by the properties of the joint and joint space themselves. The studies which report simultaneous pharmacokinetics of NSAIDs in both plasma and synovial fluid compartments are of 2 types: (1) some compare the concurrent concentrations of drugs in plasma and joint fluid after a single administration. These provide pharmacokinetic information: (2) others, which conform more closely to the therapeutic conditions, look at synovial fluid and plasma concentrations after repeated administration of the drug. Recent findings on the pharmacokinetics of NSAIDs in synovial fluid are reviewed. These studies reveal 2 types of NSAIDs, according to their pharmacokinetic behaviour. First, there are NSAIDs with a short or intermediate plasma elimination half-life. These drugs equilibrate rapidly relative to their elimination; their peak synovial fluid concentrations occur later and are lower than those in plasma. Several hours after administration there is crossover of the concentration curves, and beyond this point, concentrations in synovial fluid may exceed those in plasma. During prolonged treatment, the synovial fluid concentrations of these NSAIDs fluctuate to a much lesser extent than plasma concentrations. Secondly, there are NSAIDs with a long plasma elimination half-life; their peak concentration in synovial fluid is also lower and later than that in plasma. At steady-state their concentrations (total and free) in synovial fluid are about half those in plasma. Numerous variables must be taken into account in attempts to correlate synovial fluid NSAIDs concentrations with clinical response, including protein binding and determination of both active metabolites and (eventually) the enantiomers.

Disappearance kinetics of solutes from synovial fluid after intra‐ articular injection.

“…Most NSAIDs are highly bound to albumin [2]. The synovial fluid to plasma AUC ratio for total NSAID concentration is between 0.25 and 0.75 [1], consistent with synovial fluid/plasma concentration ratios of 0.3 to 0.7 for total proteins [3] and 0.54 to 0.8 for albumin [4].…”

“…Most studies on the pharmacokinetics of drugs in synovial fluid have been based on single or serial sampling of the knee effusion after oral administration of drug [1,5]. The present work sought to assess drug efflux from the joint after intra-articular injection.…”

“…The observed findings for flurbiprofen [22] and ketoprofen [23] are consistent with this expectation. All of the synovial fluid to plasma concentration ratios of either steady state concentrations or AUC values for total solute are reported to be less than 1 [1,4].…”

“…The concentration of non-steroidal anti-inflammatory drugs (NSAIDs) in synovial fluid is considered to be an important determinant of clinical response [1]. The diffusion of unbound drugs between the blood and the synovial fluid appears to be the main mechanism by which significant NSAID concentrations are attained and maintained in the joint [1].…”

“…The diffusion of unbound drugs between the blood and the synovial fluid appears to be the main mechanism by which significant NSAID concentrations are attained and maintained in the joint [1]. A major determinant of the steady state concentrations of a solute in the blood and synovial fluid is the relative protein binding of the NSAID in the plasma and synovial fluid.…”