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 met hods 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. P lasma and synovial fluid concentration-time data taken from the litera ture for four other nonsteroidal antiinflammatory drugs (etodolac, ibu profen, indomethacin, and tenoxicam) were also analyzed. The two metho ds of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration time curve to the area under t he plasma concentration-time curve. Both methods can be considered non compartmental because in determining the first-order exit rate constan t for the synovial fluid (the inverse of the synovial mean transit tim e), an analysis of the overall distribution and elimination characteri stics of the drug is unnecessary. Method 1 makes use of the informatio n contained in the postdistributional synovial fluid to plasma concent ration 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), w hich was not significantly different from that determined by method 2; which was 0.49 +/- 0.52 hr(-1). The steady state mean +/- S.D. diclof enac 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 no t significantly different. These values of synovial fluid exit rate co nstants result in a synovial mean transit time for diclofenac that is approximately 2 to 2.5 hours. The synovial mean transit time calculate d using method 1 from literature data for etodolac, ibuprofen, indomet hacin, and tenoxicam were 6.8, 2.2, 4.8, and 3.5 hours, respectively. The synovial mean transit times calculated by method 2 for the same dr ugs were 5.3, 3.4, 4.7, and 4.0 hours, respectively. Similar values of the synovial mean transit time of nonsteroidal antiinflammatory drugs were achieved by using either of these two methods, both of which avo id complex equation fitting which is statistically problematic in the frequently data-sparse environment of extravascular sampling.