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

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&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_maxwith 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, dJ_maJd_maxogk '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. 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.