文章基本信息

标题：Factors Determining Drug Residence in Skin during Transdermal Absorption : Studies on β-Blocking Agents
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作者：Shigenori YAGI ; Kazuki NAKAYAMA ; Yuji KUROSAKI 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1998
卷号：21
期号：11
页码：1195-1201
DOI：10.1248/bpb.21.1195
出版社：The Pharmaceutical Society of Japan
摘要：The factors determining drug residence in skin during penetraiton across rat abdominal skin were investigated using five β-blocking agents with different lipophilicities as model drugs in vivo and in vitro. The amount of β-blocking agent in the skin at steady state correlated well with lipophilicity. The distribution of β-blocking agents to the stratum corneum and the contribution of intercellular lipids in the stratum corneum to their skin distribution were also correlated with their lipophilicity, suggesting that the stratum corneum, especially intercellular lipids in the stratum corneum, wound be responsible for the residence of β-blocking agents in the skin. Furthermore, cholesterol-3-sulfate, palmitic acid, stearic acid and oleic acid were found to interact with the β-blocking agents, which are cationized under the physiological condition, and were assumed to play an important role in the skin accumulation. On the other hand, the binding to keratinocyte was so small that keratinocyte might have little effect on the skin accumulation of the β-blocking agents. Drug transport from the stratum corneum to viable skin was suggested to be regulated by the lipophilicity of these agents. To investigate the residence of these drugs in viable skin, in vitro transport studies using stripped skin were performed. The transport rate constant across viable skin to receptor cells (k₂₃) was inversely correlated with the lipophilicity of the drugs. The elimination rate constants from viable skin (k_vs) obtained in the in vivo study were much smaller than the values of k₂₃ obtained in the in vitro study, and they were inversely correlated with the binding to cytosol components of viable skin but not the lipophilicity. The viable skin-to-muscle concentration ratio of these drugs, obtained at the β-phase of the plasma concentration-time curve after intravenous administration, was also inversely correlated with the binding to the cytosol components of viable skin. These results suggest that k_vs reflects the transport from viable skin to muscle rather than to blood circulation and that the binding of drugs to cytosol components in viable skin would be one of the important factors determining the residence in viable skin.
关键词：transdermal absoprtion;topical drug residence;β-blocking agent;determining factor;stripped skin;kinetic analysis