Design of Fexofenadine Prodrugs Based on Tissue‐Specific Esterase Activity and Their Dissimilar Recognition by P‐Glycoprotein. Issue 9 (7th May 2015)

• Record Type: Journal Article
• Authors: Ohura, Kayoko; Nakada, Yuichiro; Kotani, Shunsuke; Imai, Teruko; Donovan, Maureen D.; Langguth, Peter; Polli, James E.; Tamai, Ikumi; Vig, Balvinder; Yu, Lawrence X.
• Is Part Of: Journal of pharmaceutical sciences. Volume 104:Issue 9(2015:Sep.)
• Page Start: 3076
• Page End: 3083
• Publication Date: 2015-05-07
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.24467
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3076–3083, 2015</p> </abstract>