title: Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein.
abstract: The aim of this study was to develop a suitable prodrug for fexofenadine (FXD), a model parent drug, that is resistant to intestinal esterase but converted to FXD by hepatic esterase. Carboxylesterases (CESs), human carboxylesterase 1 (hCE1) and human carboxylesterase 2 (hCE2), are the major esterases in human liver and intestine, respectively. These two CESs show quite different substrate specificities, and especially, hCE2 poorly hydrolyzes prodrugs with large acyl groups. FXD contains a carboxyl group and is poorly absorbed because of low membrane permeability and efflux by P-glycoprotein (P-gp). Therefore, two potential FXD prodrugs, ethyl-FXD and 2-hydroxyethyl-FXD, were synthesized by substitution of the carboxyl group in FXD. Both derivatives were resistant to intestinal hydrolysis, indicating their absorption as intact prodrugs. Ethyl-FXD was hydrolyzed by hepatic hCE1, but 2-hydroxyethyl-FXD was not. Both derivatives showed high membrane permeability in human P-gp-negative LLC-PK1 cells. In LLC-GA5-COL300 cells overexpressing human P-gp, ethyl-FXD was transported by P-gp, but its efflux was easily saturated. Whereas 2-hydroxyethyl-FXD showed more efficient P-gp-mediated transport than FXD. Although the structure of 2-hydroxyethyl-FXD only differs from ethyl-FXD by substitution of a hydroxyl group, 2-hydroxyethyl-FXD is unsuitable as a prodrug. However, ethyl-FXD is a good candidate prodrug because of good intestinal absorption and hepatic conversion by hCE1.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ohura
authors.affiliation: Santen Pharmaceutical Company, Ltd., Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kotani
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology; D004950:Esterases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism; D018374:LLC-PK1 Cells / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D013552:Swine; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011355:Prodrugs; D016593:Terfenadine; C093230:fexofenadine; D004950:Esterases; D002265:Carboxylic Ester Hydrolases
keywords: P-glycoprotein; bioavailability; membrane transport; metabolism; oral absorption; prodrugs