ARTICULAR PHARMACOKINETICS OF PROTEIN-BOUND ANTIRHEUMATIC AGENTS

By what mechanism do nonsteroidal anti-inflammatory drugs (NSAIDs) mov e from plasma into synovial fluid and back, and how does binding to pl asma albumin in vitro relate to articular transport in vivo? To evalua te these issues, concurrent plasma and synovial fluid data of 8 differ ent NSAIDs from 10 single-dose trials were analysed by a simple compar tmental model incorporating intra-articular volume, synovial plasma fl ow rates and protein transport. All pharmacological and physiological data were taken from published studies of chronic knee effusions in pa tients with rheumatoid arthritis. The analysis shows that these protei n-bound NSAIDs readily leave the vasculature and enter synovial fluid during each transit of synovial microvessels. The mean rate of transpo rt, 0.23 min-1, is consistent with passive diffusion at rates far in e xcess of those attributable to movement of albumin-bound drug or of th e small, free-drug fraction found by equilibrium dialysis. These findi ngs are explained by association and dissociation of NSAIDs and albumi n that occur far more rapidly than vascular transit. Ongoing dissociat ion makes bound drug available for transvascular exchange and thereby diminishes the pharmacokinetic significance of binding data obtained i n vitro.