Characterization of the transdermal transport of flurbiprofen and indomethacin.

Transdermal permeation of two types of NSAIDs, [(3)H] flurbiprofen and [(14)C] indomethacin, was examined by use of the Ussing-type chamber method. We found that the transdermal permeability in the absorptive direction (P(abs)) of [(3)H] flurbiprofen was significantly higher than that of [(14)C] indomethacin. A lower pH (5.0) on the epidermal side increased the accumulation and the P(abs) of [(3)H] flurbiprofen (18-fold and 50-fold, respectively) and [(14)C] indomethacin (18-fold and 22-fold, respectively), compared with pH 7.4. Coadministration of unlabeled flurbiprofen and indomethacin increased P(abs) of [(3)H] flurbiprofen and [(14)C] indomethacin, respectively, in a concentration-dependent manner. Similar high-affinity transport was also observed in the uptake of [(3)H] flurbiprofen by human epidermal keratinocytes (HEK001 cells). RT-PCR analysis revealed the expression of mRNA of numerous transporters including MRP, OATP, MCT and OCTN family members in hairless mouse skin, human skin and HEK001 cells. These findings support the novel hypothesis that transdermal permeation of NSAIDs is mediated by saturable transport mechanisms, which may be candidates as targets for transdermal delivery of drugs.