Stereoselective disposition of etodolac enantiomers in synovial fluid.
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.
Brocks
D R
DR
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Jamali
F
F
Russell
A S
AS
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D001168:Arthritis / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D017308:Etodolac; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007210:Indoleacetic Acids / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013237:Stereoisomerism; D013582:Synovial Fluid / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D007210:Indoleacetic Acids; D017308:Etodolac; D006820:Hyaluronic Acid