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.

Bilastine: a new H1‐antihistamine with an optimal profile for updosing in urticaria

“…While the presence of P‐glycoprotein (P‐gp) in the blood–brain barrier is beneficial in preventing the penetration of bilastine into the brain, this efflux transporter is also present in the intestine. Based on its hydrophobicity and P‐gp‐mediated efflux, the absorption of bilastine would be expected to be low as . However, the mean oral bioavailability of bilastine has been estimated to be around 61% in healthy human volunteers .…”

“…Based on its hydrophobicity and P-gp-mediated efflux, the absorption of bilastine would be expected to be low as. 17 However, the mean oral bioavailability of bilastine has been estimated to be around 61% in healthy human volunteers. 16 A possible explanation for this ( Fig.…”

Analysis of Attribution of Noopept to Substrates and Modulators of Functional Activity of Abcb1-Protein in in Vivo Experiment

“…Thus, the changes of the concentration of fexofenadine in blood characterizes the functional activity of ABCB1-protein [7,11,12].…”

“…Поэтому динамика кон-центрации фексофенадина в крови характе-ризует функциональную активность АВСВ1 белка [7,11,12]. Примечание: данные представлены в виде среднего геометрического и его 95% доверительного интервала Отсутствие статистически значимых изменений фармакокинетики фексофена-дина после курсового введения кроликам Ноопепта свидетельствует о том, что ско-рость абсорбции маркерного субстрата в кишечнике и интенсивность его экскреции не изменялись, что показывает сохранение функциональной активности ABCB1-белка на исходном уровне.…”

Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin

“…The log PC of FXD is 0.31 and its solubility is 294 mM in pH 7.4 phosphate buffer. 22 FXD was applied in the donor compartment as a suspension and kept at approximately 300 mM. Table 1.…”