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Oral NSAID pharmacokinetics

 

Clinical bottom line

After oral administration of NSAIDs, peak concentrations in plasma occur after about 1-2 hours, and then decline rapidly. Synovial fluid concentrations are similar to plasma concentrations after about four hours.

Plasma

Oral NSAIDs are rapidly absorbed. A review of ibuprofen kinetics show that plasma concentrations after a single oral dose of 400 mg of ibuprofen the peak concentration of 20-40 µg/mL occurs within 1-2 hours, but that six hours after administration the concentration is about 5µg/mL [1,2].

Synovial fluid

Synovial fluid concentrations are slower to reach maximum concentrations, which occur after 3-6 hours. Thereafter synovial fluids tend to be somewhat higher than in plasma, even up to 12 hours later. The time taken for plasma and synovial blood concentrations to equilibrate has been shown to correlate with plasma half life for the NSAIDs [2]. For aspirin it is under an hour, and for most common NSAIDs it is of the order of three to seven hours.

Table 1 shows results from some selected studies for ibuprofen, indomethacin and ketoprofen. Indomethacin and ketoprofen have lower peak plasma concentrations than ibuprofen, though synovial fluid concentrations had similar concentrations as plasma. A large recent study [3] showed that the synovial fluid and plasma concentrations of ketoprofen were similar by six hours after a single oral dose of 50 mg (Figure 1).

Table 1: Selected studies of oral kinetics of NSAIDs - plasma and tissue concentrations

Reference
Design
Results
Rolf et al. Rheumatology 1999 38: 564-567 100 patients with knee disorders requiring arthroscopy. Single application topical ketoprofen in 40, multiple applications for 5 days in 30, or single dose 50 mg oral ketoprofen Mean plasma maximum concentration with oral 2.5 µg/mL, and synovial fluid 0.35 µg/mL after oral
Whitlan et al. Clin Pharmacol Ther 1981 29: 487-492. 15 patients with arthritis given 1200 mg ibuprofen daily for two days. Blood and synovial fluid samples taken Mean serum ibuprofen concentration 20 µg/mL
Mean synovial fluid concentration 7.5 µg/L
Glass & Swannell. Br J Clin Pharmacol 1978 6:453P-454P 21 patients with osteo- or rheumatoid arthritis after single dose of 400 mg ibuprofen. Blood and synovial fluid samples taken Peak serum ibuprofen 20-60 µg/mL at 60-120 minutes, declined to below 10 µg/mL after 240 minutes.
Synovial fluid ibuprofen rose to about 10 µg/mL by 240 minutes
Emori et al. Ann Rheum Dis. 1973 32: 433-435 7 patients with rheumatoid arthritis and chronic knee effusions given 50 mg indomethacin. Blood and synovial fluid samples taken Peak serum indomethacin about 3 µg/mL at one hour, falling below 0.5 µg/mL by 4 hours.
Synovial fluid concentration at about 0.5 µg/mL by 2 hours, declining slowly with plasma concentration

Figure 1: Plasma and synovial fluid kinetics of ketoprofen

Other tissues

Maximum concentrations of ketoprofen in various tissues are shown in Figure 2. Concentrations of ketoprofen in meniscus and cartilage were well below those of synovial fluid and synovial tissue.

Figure 2: Median maximum concentrations of ketoprofen in tissue after oral administration

Comment

There are no surprises here. Oral NSAIDs are expected to be rapidly absorbed, and experience shows that they all have significant analgesic effects over a few hours in most pain states. In acute pain oral NSAIDs are highly effective, with low NNT values.

Synovial tissue is highly vascularised and receives NSAID through the general circulation. It would be expected that, after the first few hours after a dose, both synovial tissue and fluid would have similar concentrations to plasma.

References


  1. Anon. Brufen. Experimental, technical and clinical aspects of Brufen. The Boots Company plc, Nottingham, England (monograph)
  2. WJ Wallis, PA Simkin. Antirheumatic drug concentrations in human synovial fluid and synovial tissue. Clin Pharm 1983 8: 496-522.
  3. C Rolf et al. Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology 1999 38: 564-567.