Keratinized epithelial transport of β-blocking agents. I. Relationship between physicochemical properties of drugs and the flux across rat skin and hamster cheek pouch

T. Kai, T. Isami, K. Kobata, Yuji Kurosaki, T. Nakayama, T. Kimura

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Abstract

The maximum fluxes (J(max)) of β-blockers through keratinized membranes were determined in vitro and compared with their physicochemical parameters such as lipophilicity (log k'(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 J(max) with either log k'(o) or mp were observed both in intact rat skin and in intact hamster 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, dJ(max)/d(log k'(o)), for cheek pouch mucosa was greater tha 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 mucosa clarified that the primary rate-limiting barrier function might exist in the lipid layer of the stratum corneum. J(max) 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
Publication statusPublished - 1992

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Cheek
Cricetinae
Rats
Skin
Fluxes
Membranes
Pharmaceutical Preparations
Freezing
Melting point
Mucous Membrane
Permeation
Cornea
Nadolol
Pindolol
Timolol
Metoprolol
Thermodynamics
Propranolol
Solubility
Tapes

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

Keratinized epithelial transport of β-blocking agents. I. Relationship between physicochemical properties of drugs and the flux across rat skin and hamster cheek pouch. / Kai, T.; Isami, T.; Kobata, K.; Kurosaki, Yuji; Nakayama, T.; Kimura, T.

In: Chemical and Pharmaceutical Bulletin, Vol. 40, No. 9, 1992, p. 2498-2504.

Research output: Contribution to journalArticle

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