Factors determining drug residence in skin during transdermal absorption

Studies on β-blocking agents

Shigenori Yagi, Kazuki Nakayama, Yuji Kurosaki, Kazutaka Higaki, Toshikiro Kimura

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five β-blocking agents with different lipophilicities as model drugs in vivo and in vivo. 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, would 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.

Original languageEnglish
Pages (from-to)1195-1201
Number of pages7
JournalBiological and Pharmaceutical Bulletin
Volume21
Issue number11
Publication statusPublished - Nov 1998

Fingerprint

Skin Absorption
Skin
Pharmaceutical Preparations
Cornea
Cytosol
Keratinocytes
Lipids
Muscles

Keywords

  • β-blocking agent
  • Determining factor
  • Kinetic analysis
  • Stripped skin
  • Topical drug residence
  • Transdermal absorption

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Factors determining drug residence in skin during transdermal absorption : Studies on β-blocking agents. / Yagi, Shigenori; Nakayama, Kazuki; Kurosaki, Yuji; Higaki, Kazutaka; Kimura, Toshikiro.

In: Biological and Pharmaceutical Bulletin, Vol. 21, No. 11, 11.1998, p. 1195-1201.

Research output: Contribution to journalArticle

@article{234854b9a7a2448b9a078522d27724b1,
title = "Factors determining drug residence in skin during transdermal absorption: Studies on β-blocking agents",
abstract = "The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five β-blocking agents with different lipophilicities as model drugs in vivo and in vivo. 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, would 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.",
keywords = "β-blocking agent, Determining factor, Kinetic analysis, Stripped skin, Topical drug residence, Transdermal absorption",
author = "Shigenori Yagi and Kazuki Nakayama and Yuji Kurosaki and Kazutaka Higaki and Toshikiro Kimura",
year = "1998",
month = "11",
language = "English",
volume = "21",
pages = "1195--1201",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "11",

}

TY - JOUR

T1 - Factors determining drug residence in skin during transdermal absorption

T2 - Studies on β-blocking agents

AU - Yagi, Shigenori

AU - Nakayama, Kazuki

AU - Kurosaki, Yuji

AU - Higaki, Kazutaka

AU - Kimura, Toshikiro

PY - 1998/11

Y1 - 1998/11

N2 - The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five β-blocking agents with different lipophilicities as model drugs in vivo and in vivo. 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, would 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.

AB - The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five β-blocking agents with different lipophilicities as model drugs in vivo and in vivo. 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, would 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.

KW - β-blocking agent

KW - Determining factor

KW - Kinetic analysis

KW - Stripped skin

KW - Topical drug residence

KW - Transdermal absorption

UR - http://www.scopus.com/inward/record.url?scp=0031741221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031741221&partnerID=8YFLogxK

M3 - Article

VL - 21

SP - 1195

EP - 1201

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 11

ER -