Transsynovial drug distribution: synovial mean transit time of diclofenac and other nonsteroidal antiinflammatory drugs.
The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid concentration-time data taken from the literature for four other nonsteroidal antiinflammatory drugs (etodolac, ibuprofen, indomethacin, and tenoxicam) were also analyzed. The two methods of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration-time curve to the area under the plasma concentration-time curve. Both methods can be considered noncompartmental because in determining the first-order exit rate constant for the synovial fluid (the inverse of the synovial mean transit time), an analysis of the overall distribution and elimination characteristics of the drug is unnecessary. Method 1 makes use of the information contained in the postdistributional synovial fluid to plasma concentration ratio whereas method 2 is a linear pharmacokinetic model using a partial-areas analysis. The single dose mean +/- S.D. synovial fluid exit rate constant for diclofenac was 0.39 +/- 0.33 hr-1 (n = 6), which was not significantly different from that determined by method 2; which was 0.49 +/- 0.52 hr-1. The steady state mean +/- S.D. diclofenac synovial fluid exit rate constants for methods 1 and 2 were 0.43 +/- 0.18 and 0.54 +/- 0.71 hr-1 (n = 8), respectively, which were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)
Elmquist
W F
WF
Department of Pharmaceutics, University of Minnesota, Minneapolis 55455.
Chan
K K
KK
Sawchuk
R J
RJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010539:Permeability; D013583:Synovial Membrane / Q000378:metabolism*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac