Abstract
BackgroundDiclofenac is a nonsteroidal anti-inflammatory drug which is available as prescription (RX) and over-the-counter (OTC) medication for the systemic and topical treatment of painful and inflammatory conditions such as arthritis and back pain. This study was undertaken to investigate the distribution and retention of diclofenac and/or its metabolites in inflamed tissues, using the carrageenan-induced inflammation model and quantitative whole body autoradiography in rats.Methods[14C]diclofenac sodium was administrated as a single 2 mg/kg oral dose 1 h after injection of carrageenan into one front and one hind footpads and subcutaneously into the dorsum of the neck of rats. A control animal received saline injections. Three carrageenan-treated rats and one control rat were sacrificed at 1, 4, 8, and 24 h after [14C]diclofenac sodium administration (total of 4 rats/time point). The carcasses were immediately snap-frozen and prepared for cryosectioning. Lengthwise whole-body sections (40 μm thick), including all major tissues, were obtained from different levels across the body. The tissue concentrations of total radiolabeled components were determined using quantitative autoradioluminography.ResultsThe radioactivity patterns demonstrated that diclofenac and/or its metabolites preferentially distributed into the inflamed tissues. In unharmed tissues the distribution was similar in control and treated animals. The exposure, based on the areas under the tissue concentration versus time (AUC0-tlast), was 26 and 53 fold higher in the inflamed neck and inflamed footpads of treated animals than in control rats; the exposures in unharmed tissues were similar in the treated and control rats, and the AUC0-tlast was 17 fold higher in the inflamed paws than in the non inflamed footpads of the carrageenan-treated rats. The higher exposure in the inflamed tissues may be explained partly to the fact that the elimination of total radiolabeled components from inflamed tissues (t1/2 = 6 h) appeared lower than from the corresponding unharmed tissues (t1/2 = 2 h).ConclusionThis animal study demonstrated that diclofenac and/or its metabolites were rapidly and preferentially taken up and retained in inflamed tissues. Although there were theoretical considerations that mildly acidic NSAID may show some preferential distribution in inflamed tissues there was no clear experimental proof for diclofenac until the present study.
Highlights
Diclofenac is a nonsteroidal anti-inflammatory drug which is available as prescription (RX) and over-the-counter (OTC) medication for the systemic and topical treatment of painful and inflammatory conditions such as arthritis and back pain
Diclofenac belongs to the non steroidal anti-inflammatory class of drugs (NSAIDS) and is widely used in the treatment of moderate pain and inflammation, which are common symptoms of various diseases, including arthritis [1]
The present study aimed to investigate the relative distribution of diclofenac in inflamed and normal tissues in an animal model
Summary
Diclofenac is a nonsteroidal anti-inflammatory drug which is available as prescription (RX) and over-the-counter (OTC) medication for the systemic and topical treatment of painful and inflammatory conditions such as arthritis and back pain. The COX-1 isoenzyme is constitutively expressed in all tissues [4] and its activation leads to the production of prostaglandins involved in maintenance of organs systems such as protection of the stomach wall or for the kidney function. COX-2 is almost undetectable in most tissues under normal physiological conditions [6,7,8], but is induced when there is a damage in the body, leading to the production of PGs. When proinflammatory cytokines are produced, COX-2 is expressed de novo in the inflamed tissue resulting in PGs formation, which mediates pain, fever and inflammation [9]. Efficacy of oral diclofenac intake for relieving pain and inflammation or fever has been demonstrated in several clinical studies with both low dose available over-the-counter or at higher dose available by prescription [11,12,13,14,15]
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