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. These values of synovial fluid exit rate constants result in a synovial mean transit time for diclofenac that is approximately 2 to 2.5 hours. The synovial mean transit time calculated using method 1 from literature data for etodolac, ibuprofen, indomethacin, 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 drugs 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 avoid complex equation fitting which is statistically problematic in the frequently data-sparse environment of extravascular sampling.