FACTORS DETERMINING DRUG RESIDENCE IN SKIN DURING TRANSDERMAL ABSORPTION - STUDIES ON BETA-BLOCKING-AGENTS

The factors determining drug residence in skin during penetration acro ss rat abdominal skin were investigated using five beta-blocking agent s with different lipophilicities as model drugs in vivo and in vitro. The amount of beta-blocking agent in the skin at steady state correlat ed well with lipophilicity. The distribution of beta-blocking agents t o the stratum corneum and the contribution of intercellular lipids in the stratum corneum to their skin distribution were also correlated wi th their lipophilicity, suggesting that the stratum corneum, especiall y intercellular lipids in the stratum corneum, would be responsible fo r the residence of beta-blocking agents in the skin. Furthermore, chol esterol-3-sulfate, palmitic acid, stearic acid and oleic acid were fou nd to interact with the beta-blocking agents, which are cationized und er the physiological condition, and were assumed to play an important role in the skin accumulation. On the other hand, the binding to kerat inocyte was so small that keratinocyte might have little effect on the skin accumulation of the beta-blocking agents. Drug transport from th e stratum corneum to viable skin was suggested to be regulated by the lipophilicity of these agents. To investigate the residence of these d rugs in viable skin, in vitro transport studies using stripped skin we re performed. The transport rate constant across viable skin to recept or cells (k(23)) was inversely correlated with the lipophilicity of th e drugs. The elimination rate constants from viable skin (k(vs)) obtai ned in the in vivo study were much smaller than the values of k(23) ob tained in the ill vitro study, and they were inversely correlated with the binding to cytosol components of viable skin but not the lipophil icity. The viable skin-to-muscle concentration ratio of these drugs, o btained at the beta-phase of the plasma concentration-time curve after intravenous administration, was also inversely correlated with the bi nding to the cytosol components of viable skin. These results suggest that k(vs) reflects the transport from viable skin to muscle rather th an to blood circulation and that the binding of drugs to cytosol compo nents in viable skin would be one of the important factors determining the residence in viable skin.