Stereoselective Disposition of Etodolac Enantiomers in Synovial Fluid

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Abstract
The synovial fluid (SF) uptake of the chiral nonsteroidal anti‐inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R‐etodolac were up to 10‐fold greater than active S‐etodolac. Concentrations of S‐etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 ± 0.8): No such difference was seen for R‐etodolac (SF:plasma = 0.91 ± 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug‐spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S‐etodolac has greater concentrations in synovial fluid than plasma during the post‐distributive phase, which may be of possible clinical relevance.