title: Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin.
abstract: The expression of carboxylesterase (CES) and the transdermal movement of an ester prodrug were studied in rat skin. Ethyl-fexofenadine (ethyl-FXD) was used as a model lipophilic prodrug that is slowly hydrolyzed to its parent drug, FXD (MW 502). Among the CES1 and CES2 isozymes, Hydrolase A is predominant in rat skin and this enzyme was involved in 65% of the cutaneous hydrolysis of ethyl-FXD. The similarity of the permeation behavior of ethyl-FXD in full thickness and stripped skin indicated that the stratum corneum was not a barrier to penetration. However, only FXD was observed in receptor fluid, not ethyl-FXD, presumably because of the high degree of binding of ethyl-FXD in viable skin. The rate of hydrolysis of ethyl-FXD was much faster than steady-state flux, such that the influx rate was the rate-limiting process for transdermal permeation. Although Hydrolase A levels gradually increased in skin taken from rats aged from 8 to 90 weeks, variations in the expression levels of the esterase hardly affected the conversion of prodrug. The present data suggest that the slow hydrolysis of the prodrug of an active ingredient in viable skin followed by slow diffusion of active drug may provide a useful approach to topical application.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: iteruko@gpo.kumamoto-u.ac.jp.
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Ariyoshi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ohura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Santen Pharmaceutical Company, Ltd., Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakada
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D043182:Carboxylesterase / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D009924:Organ Culture Techniques; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D011355:Prodrugs; D016593:Terfenadine; C093230:fexofenadine; D043182:Carboxylesterase
keywords: mRNA; metabolism; percutaneous; permeability; phase I enzyme; prodrugs; skin