Involvement of organic anion transport system in transdermal absorption of flurbiprofen.
We previously demonstrated that transdermal permeation of flurbiprofen is mediated by a nonlinear transport mechanism(s). Here, we aimed to characterize this transport mechanism by employing an Ussing-type chamber method with tape-stripped hairless mouse skin. Transdermal permeation of [(3)H]flurbipofen was vectorial, saturable and energy-dependent, suggesting the involvement of a carrier-mediated transport system. Transdermal permeation and uptake from the epidermal side of [(3)H]flurbiprofen were inhibited by various nonsteroidal anti-inflammatory drugs (NSAIDs). The inhibitory potency did not correlate well with lipophilicity; anionic NSAIDs tended to be more potent inhibitors than non-anionic NSAIDs. The inhibition profile of both [(3)H]flurbiprofen permeation and uptake, and the Michaelis constants, were similar for a given anionic compound. These results suggest that an organic anion transport system is involved in flurbiprofen uptake from the epidermal side during the process of transdermal absorption. Efflux of [(3)H]flurbiprofen from the skin to the epidermal side, but not to the hypodermal side, increased in the presence of flurbiprofen or several anionic compounds. Such trans-stimulation may suggest the involvement of an organic anion exchanger system. Organic anion transporter 2 (OAT2) is a candidate for the exchanger involved in uptake and/or efflux of flurbiprofen in the skin.
Ito
Katsuaki
K
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Kato
Yukio
Y
Tsuji
Hiroyuki
H
Nguyen
Hai Thien
HT
Kubo
Yoshiyuki
Y
Tsuji
Akira
A
D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005480:Flurbiprofen / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009865:Oocytes / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000502:physiology*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D014982:Xenopus laevis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D029362:Organic Anion Transporters, Sodium-Independent; C490281:Slc22a7 protein, mouse; D005480:Flurbiprofen