Keratinized Epithelial Transport of β-Blocking Agents. I. Relationship between Physicochemical Properties of Drugs and the Flux across Rat Skin and Hamster Cheek Pouch

Toshiya Kai, Takenao Isami, Kyoko Kobata, Yuji Kurosaki, Taiji Nakayama, Toshikiro Kimura

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The maximum fluxes (Jmax) of β-blockers through keratinized membranes were determined in vitro and compared with their physicochemical parameters such as lipophilicity (log&o) and melting point (mp). Rat abdominal skin and hamster cheek pouch mucosa were used as the model membranes. Propranolol, metoprolol, timolol, pindolol, nadolol and agenolol were used as β-blockers with a variety of physicochemical characters. Linear relations of Jmaxwith either log&o or mp were observed both in intact rat skin and in intact hamser cheek pouch, suggesting that the lipophilicity and thermodynamic activity of a drug in the crystal state primarily affect the drug's permeation through these membranes. However, the slope, dJmaJdmaxogk '0 for cheek pouch mucosa was greater than that for rat skin, corresponding to the lack of appendageal shunt pathways in cheek pouch. Penetration studies using the delipidized membranes and the isolated stratum corneum sheet of hamster cheek pouch mocosa clarified that the primary rate-limiting barrier function might exist in the lipid layer of the stratum corneum. Jmax values for the tape-stripped and delipidized skins correlated with both the solubilities of drugs in the vehicle and with the mp, suggesting the polar porous characteristics of both model membranes. However, a theoretical approach confirmed that the contribution of an intracellular or aqueous pore route in the intact membrane to the permeation of drugs with positive lipophilic indexes is negligible.

Original languageEnglish
Pages (from-to)2498-2504
Number of pages7
JournalChemical and Pharmaceutical Bulletin
Volume40
Issue number9
DOIs
Publication statusPublished - Jan 1 1992

Keywords

  • hamster cheek pouch
  • intercellular lipid
  • isolated stratum corneum sheet
  • percutaneous absorption
  • physicochemical property
  • rat skin
  • β-blocker

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery

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