Preferential uptake of the non steroid anti-inflammatory drug diclofenac into inflamed tissues after a single oral dose in rats.
BACKGROUND
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. 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 microm 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.


RESULTS
The 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 (AUC(0-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 AUC(0-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 (t(1/2) = 6 h) appeared lower than from the corresponding unharmed tissues (t(1/2) = 2 h).


CONCLUSIONS
This 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.
Schweitzer
A
A
Department of Preclinical Development, Novartis Consumer Health, Rte Etraz, Nyon, Switzerland. alain.schweitzer@novartis.com
Hasler-Nguyen
N
N
Zijlstra
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001345:Autoradiography; D002351:Carrageenan; D004008:Diclofenac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D002351:Carrageenan